Abstract
Neurovascular unit (NVU) inflammation via activation of glial cells and neuronal damage plays a critical role in neurodegenerative diseases. Though the exact mechanism of disease pathogenesis is not understood, certain biomarkers provide valuable insight into the disease pathogenesis, severity, progression and therapeutic efficacy. These markers can be used to assess pathophysiological status of brain cells including neurons, astrocytes, microglia, oligodendrocytes, specialized microvascular endothelial cells, pericytes, NVU, and blood-brain barrier (BBB) disruption. Damage or derangements in tight junction (TJ), adherens junction (AdJ), and gap junction (GJ) components of the BBB lead to increased permeability and neuroinflammation in various brain disorders including neurodegenerative disorders. Thus, neuroinflammatory markers can be evaluated in blood, cerebrospinal fluid (CSF), or brain tissues to determine neurological disease severity, progression, and therapeutic responsiveness. Chronic inflammation is common in age-related neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia. Neurotrauma/traumatic brain injury (TBI) also leads to acute and chronic neuroinflammatory responses. The expression of some markers may also be altered many years or even decades before the onset of neurodegenerative disorders. In this review, we discuss markers of neuroinflammation, and neurodegeneration associated with acute and chronic brain disorders, especially those associated with neurovascular pathologies. These biomarkers can be evaluated in CSF, or brain tissues. Neurofilament light (NfL), ubiquitin C-terminal hydrolase-L1 (UCHL1), glial fibrillary acidic protein (GFAP), Ionized calcium-binding adaptor molecule 1 (Iba-1), transmembrane protein 119 (TMEM119), aquaporin, endothelin-1, and platelet-derived growth factor receptor beta (PDGFRβ) are some important neuroinflammatory markers. Recent BBB-on-a-chip modeling offers promising potential for providing an in-depth understanding of brain disorders and neurotherapeutics. Integration of these markers in clinical practice could potentially enhance early diagnosis, monitor disease progression, and improve therapeutic outcomes.
Introduction
Neuroinflammatory and neurodegenerative disorders are characterized by the presence of acute and chronic neuroinflammatory responses in the brain. Neuroinflammatory response is the initial response to protect the brain against damage, infection such as microbial infections/sepsis or exposure to toxins by activated glial cells and neurons (Kempuraj et al., 2020a; Gao and Hernandes, 2021; Tran et al., 2022). However, excessive and persistent glial cell activation leads to chronic neuroinflammation-associated neurodegeneration and increases disease severity of neurodegenerative disorders (Le Thuc et al., 2015; Kempuraj et al., 2016). The neuroimmune system is implicated in the development, normal functioning, aging, and integrity of the central nervous system (CNS) (Hickman et al., 2018). Chronic disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and traumatic brain injury (TBI) are neuroinflammatory and neurodegenerative disorders with dysfunctional neurons, synapses, glial cells and their networks (Pathak et al., 2022). Conditions such as Gulf War Illness (GWI) and Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are also chronic disorders that exhibit several neurological symptoms, neuroimmune dysfunction and neuroinflammation (Wirth et al., 2021; Cohen et al., 2024). The precise mechanisms underlying the pathogenesis of various neurodegenerative diseases are likely different and are currently not yet clearly understood. Different disease triggers can cause neuroinflammation and neuronal damage in different brain regions involving specific types of brain cells and pathways. Additionally, inflammatory mediators from peripheral inflammation can also influence neuroinflammation and neurodegeneration in the brain through a defective and vulnerable blood-brain barrier (BBB) (Kempuraj et al., 2017).
The BBB plays an important role in brain homeostasis by allowing selective molecules from peripheral blood into the brain parenchyma (Chin and Goh, 2018; Zapata-Acevedo et al., 2024). Neuroinflammation and neurodegenerative disorders disrupt the BBB, and increase permeability allowing the entry of immune cells, inflammatory mediators, toxic substances, and pathogens from the peripheral blood into the brain (Musafargani et al., 2020). Derangements and damage to the tight junction (TJ), adherens junction (AdJ), and gap junction (GJ) components of the BBB lead to increased BBB permeability, resulting in edema, increased neuroinflammation and neuronal damage in various brain disorders (Kempuraj et al., 2020a; Bhowmick et al., 2019). Neuroinflammation can lead to upregulation or downregulation of certain specific markers in different brain cells. Neuroinflammation can be beneficial by removing cellular debris and promoting the tissue repair process (Le Thuc et al., 2015). Neuroinflammation has also been shown to enable the proliferation and maturation of neuronal precursor cells, axonal regeneration, and remyelination over denuded axons (Yong et al., 2019). Damage/activation of glial cells, specialized brain endothelial cells, neurons, and BBB structure trigger the release of distinct markers from these cells into the cerebrospinal fluid (CSF) and blood that can be assayed by different procedures for the evaluation of disease status, progression and therapeutic efficacy. However, the dynamics of the BBB in various pathophysiological conditions are not yet clearly known. The development of BBB-on-a-chip modeling in the last decade has the potential for further understanding of BBB dynamics in pathophysiological conditions and neurotherapeutics (Peng et al., 2022; Ohbuchi et al., 2024). In this review, we present markers of neurons, glial cells, neurovascular unit (NVU), BBB proteins, neuroinflammation, and neurodegeneration associated with acute and chronic brain disorders.
Neuroinflammation and neurodegeneration markers
Neurogenesis is a turnover process that generates new neurons during adulthood, maintaining the integrity of the brain. Neurodegeneration is a slow and progressive dysfunction, loss of axons and neurons, which is accelerated by the aging process as well as the neuroinflammatory process (Culig et al., 2022). Mature neuronal markers include nuclear protein neuronal nuclei (NeuN; nuclei), neuron-specific enolase (NSE; cell bodies/soma), neurofilament light (NfL; axons), TUJ1 (class III beta-tubulin; cytoskeleton), tau (axon, cell body, dendrites), spectrin breakdown products (SBDPs; axons), and microtubule-associated protein 2 (MAP2; dendrites) which indicate specific parts of the neuron or damage (Zetterberg and Blennow, 2016; Figure 1). Synaptic markers include synaptosomal-associated protein (SNAP25), synaptophysin (SYP), and neuroligin (Zetterberg and Blennow, 2016). Neurodegeneration can be assessed by neuronal markers MAP2, NfL, TUJ1, and SYP. However, certain markers such as amyloid precursor protein (APP), amyloid β (Aβ) and tau are more specific to AD pathology. Synaptic disorder, synaptic loss and cognitive decline are common manifestations of neurodegenerative disorders (Dejanovic et al., 2024). Neuronal damage, neurodegeneration and neuronal loss have been reported in AD, PD and TBI. Nearly 19.5% of soldiers deployed in Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) were exposed to blast traumatic brain injury (bTBI) (Kempuraj et al., 2020a). Certain conditions such as TBI and stress are risk factors for the onset of progressive neurodegenerative disorders including AD and PD or dementia or can exacerbate the existing AD, PD pathologies and dementia (Kempuraj et al., 2020b; Brett et al., 2022). The levels of ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) in the blood are U.S. Food and Drug Administration (FDA)-approved biomarkers for mild TBI (mTBI) (Wang et al., 2021a). Certain brain injury/TBI markers include UCH-L1, NSE, erythrocyte membrane protein band 4.1 (EPB41) for cell body/soma injury, NfL, tau, myelin basic protein (MBP) for axonal injury, SNCA for synaptic injury, GFAP, S100B for glial cell injury and inflammatory cytokines and neurotoxic mediators (for inflammation) (Silvestro et al., 2024; Zetterberg and Blennow, 2016). Certain chronic neuroimmune conditions such as ME/CFS and GWI are associated with neuroinflammation but may not have apparent neurodegeneration (Cohen et al., 2024; O’Callaghan and Miller, 2019). Positron emission tomography (PET) and magnetic resonance spectroscopic (MRS) neuroimaging allow for a non-invasive “read” of the brain for neuroinflammatory processes and neuronal integrity in brain diseases (Van Der Naalt, 2015; Lee et al., 2024).
FIGURE 1
Activation of glial cells such as microglia and astrocytes lead to the release of molecules that trigger neuroinflammatory response and neuroinflammation. Both microglia and astrocytes can function either as neurotoxic (proinflammatory) M1 microglia and A1 astrocytes or as anti-inflammatory (neuroprotective) M2 microglia and A2 astrocytes phenotypes (Kwon and Koh, 2020; Guo et al., 2022). M1 microglia and A1 astrocytes release proinflammatory and neurotoxic molecules, whereas M2 microglia and A2 astrocytes produce neurotrophic and neuroprotective molecules that support neuronal growth and survival (Kwon and Koh, 2020). The M1/A1 or M2/A2 status (phenotype) of these cells can change during disease progression and can alter the severity of neuroinflammatory and neurodegenerative diseases (Kwon and Koh, 2020). Resting astrocytes (A0) become functional astrocytes (A1 and A2) by stimulation (Ding et al., 2021; Figure 2). Senescent dystrophic microglia have abnormal morphology with deramification (thin and short branches) and fragmented cytoplasm (Woollacott et al., 2020). The number of dystrophic microglia increases in neurodegenerative disorders such as AD in which many microglia are dysfunctional and senescent (Woollacott et al., 2020; Shahidehpour et al., 2021). Neuroinflammatory and neurodegenerative conditions impact the NVU which consists of microvascular specialized endothelial cells with BBB complex, pericytes and astrocytes (Bhowmick et al., 2019; Kempuraj et al., 2020a; Kempuraj et al., 2024). Disruption of NUV and BBB, glial activation and dementia have been reported in the recent coronavirus disease 2019 (COVID-19)/Long COVID conditions caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Kempuraj et al., 2024; Owens et al., 2024; Theoharides and Kempuraj, 2023; Shi et al., 2023; Zingaropoli et al., 2022). Inflammation in the brain activates glial cells to release inflammatory mediators which activate endothelial cells to express adhesion molecules and attract the peripheral blood leukocytes to the inflammatory site in the brain. Activated endothelial cells lead to loss of vascular integrity, increased adhesion molecule expression and cytokine and chemokine release including C-C motif ligand 2 (CCL2), CCL3, and interleukin-8 (IL-8) (Theofilis et al., 2021; Alsbrook et al., 2023). Cerebral endothelial cells express toll-like receptors (TLRs), chemokine receptors C-X-C motif chemokine receptor 1 (CXCR1), CXCR2, CXCR3, CCR3, CXCR4, and tumor necrosis factor receptors (TNFRs) TNFR1 and TNFR2. Pericytes cover the micro vessels in the brain and express various contractile and cytoskeleton proteins such as α-smooth muscle actin, nestin, myosin, vimentin, and desmin, cell surface neural/glial antigen 2 (NG2), platelet derived growth factor receptor beta (PDGFRβ), cluster of differentiation 13 (CD13), and CD146 (Alarcon-Martinez et al., 2021). Pericytes play a role in regulating the BBB, angiogenesis, removal of toxins, blood flow, stem cells, and neuroinflammation (Bhowmick et al., 2019). Pericytes can differentiate into microglia-like cells with phagocytic activity indicating that pericyte loss may increase leukocyte infiltration (Alsbrook et al., 2023). Additionally, pericytes can express TLR4 and exert a proinflammatory response. Pericyte damage can lead to BBB dysfunction allowing the influx of neurotoxic molecules in the brain from the peripheral blood. Astrocytes are the most abundant cells in the brain and are involved in the formation, maintenance and BBB permeability (Schiera et al., 2024; Rauf et al., 2022). Increased GFAP expression, an astrocyte marker, activates astrocytes and releases IL-1β, IL-6 and TNF (Giovannoni and Quintana, 2020). Astrocytes also induce anti-inflammatory effects and regulate neurotransmitter homeostasis such as glutamate. Peripheral inflammation may lead to brain endothelial activation, allowing peripheral blood inflammatory factors to enter the brain, activate perivascular macrophages and microglia, and initiate neuroinflammation without any primary injury or disease in the brain (Mayer and Fischer, 2024). Microglia are the primary innate/resident immune cells in the brain that first respond to injuries in the brain (Rauf et al., 2022). Microglia constantly sense changes in the brain tissue microenvironment for housekeeping function that helps neuronal health and functions (Mayer and Fischer, 2024). Microglia can express inflammatory cytokines and chemokines such as TNF, IL-1, IL-6, CCL2, and IL-18 to stimuli and they also express activation marker sTREM2 (soluble triggering receptor expressed on myeloid cells 2).
FIGURE 2
Understanding NVU/BBB dynamics in the brain’s pathophysiological conditions will improve the treatment options for brain disorders. In addition to the cells in the brain, infiltration of immunocytes, cytokines, chemokines and neurotoxic molecules from the periphery also activate glial cells, further releasing additional inflammatory mediators that accelerate neuroinflammation in the brain. Pathogenic substances that enter from the periphery to the brain also enhance inflammatory response in the brain (Kempuraj et al., 2017). There are several types of biomarkers including immunochemical analysis in tissues that involve tissue biopsy or post-mortem tissue, blood (minimally invasive)/CSF (invasive) based biomarkers, physical by physical examination such as cognitive test, urine, and brain imaging such as MRI (Chahine et al., 2014). Extracellular vehicles (EVs) released from brain cells can be detected in the blood and CSF and used as a marker for brain disorders (Gamez-Valero et al., 2019; Ollen-Bittle et al., 2022). Additionally, genomic and proteomic analysis provides molecular level biomarkers with next-generation sequencing and mass spectrometry procedures for neurological disorders (Chase Huizar et al., 2020). Abnormally activated glial cells can secrete disease-specific proteins that can be used as a novel biomarker (Kim et al., 2020). Recent progress in proteomic research has the potential for the development of novel
biomarkers for brain disorders (Kim et al., 2020). MicroRNAs (miRNAs) play an important role in inflammatory response in neuroinflammation (Su et al., 2016). Liquid biopsies such as exosomal miRNA are important biomarkers for many diseases including neurological diseases (Malhotra et al., 2023; Zhou et al., 2024).
Table 1 provides various markers of neurons, astrocytes, microglia, neuroinflammation, neurodegeneration, the NVU, and the BBB complex with their dysfunctions and associated neuropathology. This table also includes some membrane proteins, secreted proteins, signaling proteins and structural proteins associated with brain cells. Effective neurotherapeutic options should ideally target the BBB complex, address the damage and derangement of BBB proteins, and reduce BBB dysfunction.
TABLE 1
| No. | Markers | Cells expressed and location | Marker type | Diseases/pathologies associated | References |
| 1 | NeuN (neuronal nuclear protein) | Specific neuronal marker (mature)−nuclear and perinuclear cytoplasm | Protein-neuronal marker-neuronal differentiation marker, mature neuron marker | Neuro-oncology, cancer diagnosis, cognitive impairment, dementia | Duan et al., 2016; Gusel’nikova and Korzhevskiy, 2015; Yang et al., 2024 |
| 2 | MAP-2 (microtubule-associated protein 2) | Neurons (mature)/dendrites | Protein–neuron marker, found in somatodendritic compartment of neurons | Neurodegeneration | Nguyen et al., 2022; Johnson and Jope, 1992; Geisert et al., 1990 |
| 3 | NFL (neurofilament light chain) | Neurons−myelinated axons−(mature) | Neuronal cytoskeleton protein in myelinated axons maintains neuronal shape and size, the transmission of a nerve impulse along axons, biomarker for neurodegeneration | Cognition, neurodegenerative indicators, monitor disease progression, MS, neurodegenerative dementia, stroke, TBI, amyotrophic lateral sclerosis and PD. Chronic traumatic encephalopathy (CTE), COVID | Ramani et al., 2021; Khalil et al., 2018; Shahim et al., 2020; Shahim et al., 2024; Mullard, 2023; Elahi et al., 2020; Zingaropoli et al., 2022 |
| 4 | MBP (myelin basic protein) | Neurons-myelin sheath/in white matter−produced by oligodendrocytes | Protein, a marker of brain tissue injury, cerebral damage, and demyelination | MS/demyelinating diseases | Kim and Kim, 2024; Wasik et al., 2020; Bohnert et al., 2021 |
| 5 | UCHL1 (ubiquitin C-terminal hydrolase L1) | Neurons (mature)-enzyme, highly expressed in the brain | A brain-specific enzyme, for axonal/neuronal repair after injury, axonal transport, memory, protect neurons | TBI, PD, AD -diffuse injuries | Hossain et al., 2024; Mi and Graham, 2023; Malhotra et al., 2024; Buneeva and Medvedev, 2024 |
| 6 | βIII-tubulin (Tuj-1) | Differentiating neurons, early stages of neurogenesis and axonal growth | Earliest neuronal differentiation marker in CNS and PNS, neuronal identity marker | Tumor | Duly et al., 2022; Hausrat et al., 2021 |
| 7 | TH (tyrosine hydroxylase) | Neuronal marker/substantia nigra/midbrain | B -tubulin protein family, enzyme | PD | Nagatsu et al., 2019; Thangavel et al., 2024 |
| 8 | NPY (neuropeptide Y) | Neurons (GABAergic), cerebral cortex, hippocampus, hypothalamus, brain stem, thalamus | Peptide (abundant in CNS) | Neurogenesis, stress, anxiety, endothelial dysfunctions, brain disorders, depression | Shende and Desai, 2020; Morales-Medina et al., 2010; Thorsell, 2010 |
| 9 | Neuroligins 1-4 | Neurons-dendrite-postsynaptic, cortical astrocytes | Synaptic cell adhesion molecule, neuronal damage marker | Cognitive impairments, | Stogsdill et al., 2017; Sudhof, 2008; Sindi et al., 2014 |
| 10 | Neurexin | Neurons-axon-pre-synaptic | Synaptic cell adhesion molecule | Cognitive impairments, autism spectrum disorder (ASD) | Craig and Kang, 2007; Zhang et al., 2023; Cao and Tabuchi, 2017; Sindi et al., 2014; Reissner et al., 2013 |
| 11 | NSE (neuron specific enolase) | Neurons-neurons and their axonal and dendritic processes, astrocytes. The cytoplasm of neurons/neuronal damage indicator/tumor & prognosis | Enzyme, neural maturation index | Neuronal damage marker, cognitive disorder, neurotrauma, spinal cord injury, neuroendocrine tumors | Babkina et al., 2024; Haque et al., 2016; Dichev et al., 2020; Liu et al., 2024 |
| 12 | Amyloid beta (Aβ) peptide 1-42 (from amyloid precursor protein)/ APs (amyloid plaques) | Peptide−extracellular | Peptide, cognitive dysfunction marker, AD biomarker | AD, Parkinson’s disease dementia (PDD) | Varesi et al., 2022; Teunissen et al., 2022; Yadollahikhales and Rojas, 2023 |
| 13 | NFTs (neurofibrillary tangles) | Neurons-intracellular/lesions | Intracellular hyperphosphorylated tau-containing NFTs | AD, hallmark of AD | Korczyn and Grinberg, 2024; Mary et al., 2024; Mehta and Mehta, 2023; Kempuraj et al., 2019 |
| 14 | Tau, phosphorylated Tau, total Tau | Neurons (mature)/microtube protein-accumulate & form NFTs | Protein, AD biomarker | AD, TBI | Teunissen et al., 2022; Varesi et al., 2022; Alonso et al., 2024; Granholm and Hamlett, 2024; Munoz Pareja et al., 2024 |
| 15 | Total α-synuclein phosphorylated α-synuclein | Dopaminergic neurons, cortical neurons, substantia nigra, endothelial cells | Neuronal presynaptic cytoplasmic protein, synaptic signaling, non-fibrillar α-synuclein is cytotoxic | Neurodegeneration, PD | Praschberger et al., 2023; Morris et al., 2024; Negi et al., 2024 |
| 16 | Lewy body (fibrillar aggregates) | Intraneuronal protein (α-synuclein) in nigrostriatal neurons | Aging, a hallmark of PD, a marker of neuronal degeneration | PDD dementia with Lewy bodies, Dementia with Lewy bodies (DLB), neurodegenerative disorder | Wakabayashi et al., 2013; Agarwal et al., 2024 |
| 17 | Parkin | Primarily in brain cells – cytosolic, neuritis, synaptic vesicles | Mitochondrial metabolism, neuroprotective protein | PD | Wakabayashi et al., 2013; Song and Krainc, 2024 |
| 18 | ApoE (apolipoprotein E)/ApoE e4 | Astrocytes, macrophages, adipocytes | Protein, a risk factor for AD/Lipid/cholesterol transporter in blood | AD, BBB disruption, cognitive decline | Zhou et al., 2023; Jackson et al., 2022 |
| 19 | GFAP (glial fibrillary acidic protein) | Astrocytes | Protein, maintain shape and motility of astrocytic process, BBB integrity | Focal brain lesions, TBI, an early biomarker for PD | Bhowmick et al., 2019; Shahim et al., 2024; Lotankar et al., 2017; Hossain et al., 2024; Elahi et al., 2020; Munoz Pareja et al., 2024; Sharma et al., 2022 |
| 20 | GFAP-BDP (GFAP breakdown products) | Astrocytes | Astrocyte cytoskeleton, gliolysis | TBI, intracranial injury, PD | Lotankar et al., 2017; Okonkwo et al., 2013; McMahon et al., 2015; Boutte et al., 2016 |
| 21 | DJ-1 (protein deglycase) | All cells including brain cells (neurons, glial cells) | Protein, neuroprotective role | Anti-oxidative properties, neurodegeneration | Lind-Holm Mogensen et al., 2023; Repici and Giorgini, 2019; Antipova and Bandopadhyay, 2017 |
| 22 | S100β | Mature astrocytes that ensheath blood vessels, neurons | Cytoplasmic/nuclear protein, trophic and toxic effects, neurite outgrowth, prolonged neurite survival | Acute brain damage, CNS & BBB damage marker, TBI, neuropsychiatric disorders, neurodegeneration | Rothermundt et al., 2003; Hossain et al., 2024; Munoz Pareja et al., 2024 |
| 23 | S100A8/S100A9 (MRP8, MRP9- calprotectin) | Neutrophils and monocytes/macrophages | 100 family, Trigger chemotaxis and phagocytic migration | Inflammatory diseases, rheumatoid arthritis, trauma, stress, cancer | Shabani et al., 2018; Xia et al., 2024; Shepherd et al., 2006 |
| 24 | AQ4 (aquaporin 4) | Astrocyte end-feet/blood vessel | Water channel protein, the most abundant molecule in the brain at the astrocytic membrane at BBB, adhesion molecule, synaptic plasticity | Edema, BBB damage, dementia, TBI, neuroinflammation, neurodegenerative disorders | Bhowmick et al., 2019; Lapshina and Ekimova, 2024; Nagelhus and Ottersen, 2013; Kitchen et al., 2020; Yang et al., 2016; Papadopoulos and Verkman, 2007; Bhend et al., 2023; Cibelli et al., 2021; Ikeshima-Kataoka, 2016 |
| 25 | NGF (nerve growth factor) | Growth factor for nerve, from neurons of cortex and hippocampus | Regulate neuroimmune response | AD, wound repair | Rocco et al., 2018; Sims et al., 2022; Ding et al., 2020; Bruno et al., 2023 |
| 26 | BDNF (brain-derived neurotrophic factor) | Major growth factor, a growth factor for neurons/neurogenesis (proliferation, differentiation and survival), neurotrophic, regulate synaptic connections, synaptic transmission, synaptic plasticity, released from neurons and glia | Growth factor, biomarker for PD, reduced in PD. neuronal maintenance, neuronal survival, plasticity, and neurotransmitter regulation. | AD, PD, Psychiatric and neurodegenerative disorders | Elahi et al., 2020; Albini et al., 2023; Lima Giacobbo et al., 2019; Zuccato and Cattaneo, 2009 |
| 27 | GDNF (glial cell-derived neurotrophic factor) | For neuronal survival, the striatum, acts on dopaminergic/motor neurons | Growth factor, neuroprotection | PD (treatment)–neurodegenerative disorders | Allen et al., 2013; Cintron-Colon et al., 2020; Ford et al., 2023; Fusco and Paldino, 2024 |
| 28 | SP (substance P) | Neurons, immune cells | Peptide, promotes wound healing, pain modulation | Anxiety disorder, major depressive disorder (MDD), post-traumatic stress disorder (PTSD), inflammation, nociception, Pain sensitivity, psychiatric conditions | Safwat et al., 2023; Mashaghi et al., 2016; Humes et al., 2024; Liao et al., 2024; Taracanova et al., 2018 |
| 29 | NT (neurotensin) | Endothelial cells, peptide in CNS and GI tract, pre-post synaptic vesicles | Peptide/neurotransmitter, activate microglia | Pain, inflammation, stress-related disorder | Kyriatzis et al., 2024; Iyer and Kunos, 2021; Theoharides et al., 2016 |
| 30 | Ng (neurogranin) | Neuron, synaptic marker, marker of synaptic degeneration | Protein, synaptic plasticity, synaptic regeneration | Synaptic dysfunction, synaptic damage, AD, PD, depression, TBI, stroke | Xiang et al., 2020; Lista and Hampel, 2017; Hellwig et al., 2015; Hawksworth et al., 2022 |
| 31 | SNAP-25 (synaptosomal-associated protein-25) | Neuron, synaptic marker, neurotransmission | Protein | Synaptic dysfunction, synaptic damage, psychiatric disorders, AD, schizophrenia, epilepsy, attention deficient hyperactivity disorder | Hawksworth et al., 2022; Kadkova et al., 2019; Noor and Zahid, 2017 |
| 32 | NTF3/4 (neurotropin-3/4) | Nerve growth factor, neuroplasticity, NGF family, induce the survival, development, and function of neurons | Neurotrophins | Neurodevelopmental disorders, major depressive disorder | Wysokinski, 2016 |
| 33 | Fibronectin | Pericytes, endothelial cells, astrocytes (in vasculature in CNS) | Soluble glycoprotein, ECM protein, neuroprotection, axonal regeneration, BBB/vascular injury marker; extracellular protein, activates microglia and invading macrophages in the brain, wound healing | CNS-vascular injury/stroke | George and Geller, 2018; Patten and Wang, 2021; Dai et al., 2024; Wei et al., 2023a; Chu et al., 2023 |
| 34 | GMF (glia maturation factor) | Astrocytes | Proinflammatory brain protein, activate microglia and macrophages | Neuroinflammation, neurodegenerative diseases, TBI | Fan et al., 2018; Kempuraj et al., 2018; Ahmed et al., 2020; Selvakumar et al., 2020a; Thangavel et al., 2017; Selvakumar et al., 2020b |
| 35 | CXCL1 C-X-C motif chemokine ligand 1 (fractalkine; FKN) | Neuron, astrocytes | Chemokine, microglia activation | Brain injury, neuroinflammation | Michael et al., 2020; Huang et al., 2023; Chen et al., 2023 |
| 36 | Progranulin | Motor neurons | Neurotrophic factor/growth factor, anti-inflammatory protein, neuronal survival, role in synapse | Neurodegenerative diseases - dementia, Amyotrophic lateral sclerosis (ALS), AD | Wang et al., 2021b; Nabizadeh et al., 2024 |
| 37 | MMPs (matrix metalloproteinases) MMP-9 | CNS−from neurons endothelial cells, astrocytes, microglia, oligodendrocytes | Enzymes, beneficial synaptic plasticity, learning, and memory. critical for tissue formation, neuronal network remodeling, and BBB integrity, detrimental diseases, inflammation, neuronal death | Pathologic role in CNS diseases, neurodegeneration, AD, brain neurodegenerative diseases | Vafadari et al., 2016; Aksnes et al., 2023; Rempe et al., 2016; Norden et al., 2016; Sharma et al., 2022 |
| 38 | Iba1 (ionized calcium-binding adaptor molecule 1) | Microglia, macrophages | A marker of microglia/macrophages | Neuroinflammation, indicator of microglia activation | Zhang et al., 2021; Thangavel et al., 2012 |
| 39 | TMEM119 (transmembrane protein 119; Iba-1 & CD68 + microglia) | Microglia, a marker of microglia subset−M1 (CD80) & M2 (CD163, CD209)−brain or blood-derived | Only brain resident microglia express TMEM119 (not blood-derived macrophages) | AD (not in MS), TBI, ALS | Ruan and Elyaman, 2022; Satoh et al., 2016; Togawa et al., 2024 |
| 40 | TREM2 (triggering receptor expressed on myeloid cells 2) | Microglia | Microglial function, receptor for a multitude of ligands enhancing their phagocytic activity | Neuroinflammatory diseases, AD, tau-mediated pathology | Pocock et al., 2024; Shi et al., 2024; Matteoli, 2024; Jain et al., 2023 |
| 41 | P2RY12 (purinergic receptor P2Y, G-protein coupled 12) | Microglia, oligodendrocytes– receptor, immune cells | Receptor | Microglial activation, neuroinflammation, AD | Gomez Morillas et al., 2021; Kenkhuis et al., 2022; Cattaneo, 2015 |
| 42 | CD11b | Microglia | Integrin molecule, role in cell migration, adhesion, and transmigration, bind to endothelial cells | Stroke, TBI | Korf et al., 2022; Kumar et al., 2017 |
| 43 | CD80 (M1 microglia) | Microglia M1 type, immune cells | Membrane protein | Inflammatory type | Yamaguchi et al., 2024 |
| 44 | CD162/CD209 (M2 microglia) | Microglia M2 type, surface receptor | Adhesion molecule | Anti-inflammatory type, immune response | Satoh et al., 2016 |
| 45 | CD40 | Microglia | Immunoregulatory protein | Neurological diseases, AD | Benveniste et al., 2004; Ots et al., 2022; Togo et al., 2000 |
| 46 | CD45 | Microglia | Pro-phagocytic and protective role | AD | Rangaraju et al., 2018 |
| 47 | CD68 | Microglia, monocytes/macrophages | Protein | ALS, carcinoma | Swanson et al., 2023; Waller et al., 2019 |
| 48 | OX-42 | Microglia | Microglia marker | Brain disorders | Robinson et al., 2014; Elkabes et al., 1996 |
| 49 | Endothelin-1 | Endothelial cells, some types of neurons, epithelial cells of the choroid plexus, and endothelial cells of micro vessels | Neuropeptide, neurovascular unit | Post COVID syndrome/Long COVID, neuroinflammation, neurodegenerative diseases, AD, TBI, ME/CFS | Banecki and Dora, 2023; Hostenbach et al., 2016; D’Orleans-Juste et al., 2019; Haffke et al., 2022; Custodia et al., 2023 |
| 50 | vWF (von-Willebrand Factor) | Endothelial cells, Endothelial injury, | Neurovascular unit, endothelial cell marker | COVID-19, neuroinflammation, neurotrauma/TBI, angiogenesis, dementia, AD | Bhowmick et al., 2019; Wolters et al., 2018 |
| 51 | Ang-2 (angiopoietin-2) | Endothelial cells, extracellular protein | Growth factor, promote neovascularization, role in angiogenesis and inflammation, neurovascular unit | Increase vascular permeability, BBB leakage, neuronal damage, AD, ME/CFS, Long COVID | Van Hulle et al., 2024; Haffke et al., 2022; Scholz et al., 2015; Ju et al., 2014; Hegen et al., 2004 |
| 52 | Endosialin (CD248)/tumor endothelial marker 1 (TEM1) | Endothelial cells, tumor cells, vessels covering pericytes, pericytes | Endothelial marker, stromal fibroblast marker, pericyte proliferation | Tumor growth, brain tumor | Kontsekova et al., 2016; MacFadyen et al., 2005; Tomkowicz et al., 2010 |
| 53 | ESM-1 (endocan) | Endothelial cells | Neurovascular unit | Post-COVID-19 syndrome, ME/CFS | Haffke et al., 2022 |
| 54 | ICAM-1 (CD54/intercellular adhesion molecule-1) | Endothelial cells, astrocytes, microglia | Neurovascular unit | Inflammation, neuroimmune response; BBB, AD, PD | Sharma et al., 2022; Zhang et al., 2024; Janelidze et al., 2018 |
| 55 | VCAM-1 (CD106/vascular cell adhesion molecule-1) | Endothelial cells | Neurovascular unit | Inflammation, neuroimmune response; BBB, AD | Sharma et al., 2022; Janelidze et al., 2018 |
| 56 | NRP1 (neuropilin 1) | Endothelial cells | Neuronal axon growth, receptor for VEGF, vascularization | Angiogenesis, COVID-19, cancer/metastasis, vascular permeability, stroke | Domingues and Fantin, 2021; Al-Thomali et al., 2022; Cantuti-Castelvetri et al., 2020; Lim et al., 2021 |
| 57 | PDGFRβ (platelet-derived growth factor-beta) | Pericytes | Neurovascular unit | Neuroinflammation | Bhowmick et al., 2019; Sharma et al., 2022; Kempuraj et al., 2021 |
| 58 | NG2 (neural-glial factor/antigen 2) | Pericytes, other cells, non-neuronal cells, during development, NG2 cells can differentiate into oligodendrocytes, astrocytes and neurons. polydendrocytes, oligodendrocytes progenitor cells | NG2 cells may differentiate into neurons even in developed brain, NG2 cells also differentiate into astrocytes | Neuroinflammation, neurogenesis potential, AD, PD, MS, cerebrovascular disease | Hu et al., 2023; Zhang et al., 2022; Rigo et al., 2024; Mira et al., 2021; Wang and He, 2009; Bhowmick et al., 2019 |
| 59 | CD13 | Pericytes, endothelial cells, monocytes | Cell adhesion, monocyte/leucocyte trafficking across endothelial cells at the site of injury | Neuroinflammation | Mina-Osorio et al., 2008 |
| 60 | ZO-1 (zonula occludens-1) | BBB-endothelium, microvascular endothelial cells | Tight junction protein, Zonula occludens-1 binds to the actin cytoskeleton for BBB integrity & permeability | Neuroinflammation, edema, BBB disruption, psychotic disorders, AD, TBI | Bhowmick et al., 2019; Sharma et al., 2022; Alluri et al., 2024; Aydogan Avsar and Akkus, 2024; Rochfort and Cummins, 2015; Kempuraj et al., 2021; Asghari et al., 2024; Dithmer et al., 2024 |
| 61 | JAM-A (junctional adhesion molecule-A) | BBB-endothelium | Tight junction protein | Neuroinflammation, edema, BBB disruption, AD, TBI | Bhowmick et al., 2019; Kempuraj et al., 2021; Yeung et al., 2008; Dithmer et al., 2024 |
| 62 | Claudins/Claudin-5 | BBB-endothelium, microvascular endothelium | Tight junction protein | Neuroinflammation, edema, BBB disruption, neurological diseases, AD, TBI | Bhowmick et al., 2019; Haruwaka et al., 2019; Hashimoto et al., 2023; Wakayama et al., 2022; Asghari et al., 2024; Dithmer et al., 2024; Tachibana et al., 2024; Ohbuchi et al., 2024 |
| 63 | Occludin | BBB-endothelium | Tight junction protein | Neuroinflammation, edema, BBB disruption, AD, TBI | Bhowmick et al., 2019; Asghari et al., 2024; Dithmer et al., 2024; Li et al., 2018 |
| 64 | N-cadherin/VE-cadherin (vascular Endothelial cadherin) | BBB-endothelium | Adherens junction protein-assembly of AJ and BBB architecture, endothelial cell contact, endothelial injury marker of preclinical AD, cell proliferation, apoptosis | Neuroinflammation, edema, BBB disruption, AD, cognitive impairment | Asghari et al., 2024; Rho et al., 2017; Tarawneh et al., 2022; Bei et al., 2023 |
| 65 | Connexin-43 | BBB-endothelium; neurons, astrocytes & microglia form gap junction | Gap junction protein, | Neuroinflammation, edema, BBB disruption, promote immune quiescence of the brain by astroglial connection 43 | Bhowmick et al., 2019; Boulay et al., 2015; Cibelli et al., 2021 |
| 66 | IL-33 | Damaged cells, immune cells, damaged astrocytes, Th2 cells, mast cells, endothelial cells | Cytokine, IL-1 superfamily, inflammatory, alarmin signal, neuroprotective effects, recruitment of microglia/macrophage, dual role as pro and anti-inflammatory effects | Tissue damage, activation of microglia, astrocytes, macrophage, endothelial cells and mast cells, neuroinflammation, cognitive impairments, TBI | Erenler and Baydin, 2020; Fu et al., 2016; Jiao et al., 2020; Vainchtein et al., 2018; Wicher et al., 2017; Reverchon et al., 2020; Rao et al., 2022 |
| 67 | ST2 (soluble ST2) | Blood | IL-33 receptor, inflammatory, IL-33/ST2 axis protective through Treg | Inflammatory, tissue damage, AD, TBI | Fu et al., 2016; Xiong et al., 2014; Xie et al., 2022; Tan et al., 2023; Cao et al., 2018 |
| 68 | IL-36 | Brain cells, microglia, immune cells-monocytes, immune cells | Cytokine, IL-1 superfamily, inflammatory response, can activate microglia | Inflammation | van de Veerdonk et al., 2018; Zhou and Todorovic, 2021; Bozoyan et al., 2015 |
| 69 | IL-37 | PBMCs, macrophages, various tissues | Immunosuppressive cytokine, IL-1 superfamily, anti-inflammatory, neurotherapeutic agent | Inflammatory diseases, improve neuroprotection, suppress inflammation/innate immunity, stroke, AD, ASD | Brunt et al., 2023; Zhang et al., 2019; Lonnemann et al., 2022; Li et al., 2022; Tsilioni et al., 2019 |
| 70 | IL-38 | IL-1 family member, brain | Cytokine, IL-1 superfamily, anti-inflammatory | Suppress neuroinflammation, ASD. Cardiovascular and autoimmune diseases, chronic inflammatory diseases | van de Veerdonk et al., 2018; Tsilioni et al., 2020; Zare Rafie et al., 2021; Xu and Huang, 2018 |
| 71 | ACE-2 (angiotensin-converting enzyme 2) | Receptor for SARS CoV-2, cell surface, endothelium, glial cells, neurons | Enzyme (protective) | COVID-19, long COVID, lung injury, renal dysfunction, protective role in fibrosis | Ahmad et al., 2022; Gupta et al., 2024; Tyagi et al., 2023; Varillas-Delgado et al., 2023; Tziolos et al., 2023; Wei et al., 2023b; Keller et al., 2023 |
| 72 | VEGF (vascular endothelial growth factor) | Many cells-macrophages, mast cells | Vascular health, angiogenic factor, vasculogenesis, neuroprotective, rescue synaptic dysfunction, blood vessel formation, migration, proliferation of endothelial cells | Angiogenesis, cancer, arthritis, neuroinflammation, MS, AD | Sharma et al., 2022; Amini Harandi et al., 2022; Requena-Ocana et al., 2022; Elahi et al., 2020; Echeverria et al., 2017; Martin et al., 2021 |
| VEGF-A | Help recover the brain after severe injury, biomarker for cognitive impairment in alcohol use disorder | mTBI, cognitive function | Sun et al., 2024; Sun et al., 2022 | ||
| VEGFR2 | Receptor for VEGF | AD | Cho et al., 2017; Harris et al., 2018 | ||
| 73 | Osteopontin (OPN; CD44) | Microglia, mast cells, macrophages, activated T-cells, NK cells, and dendritic cells, in bone, astrocytes | Soluble cytokine, glycoprotein, adhesive protein in ECM, microglia activation marker, mast cell mediator, matrikine/soluble cytokine, regulate proliferation, migration and survival of astrocytes, regulate immune cell migration, communication, and response to brain injury | Mast cell disorders, injury, neuroinflammatory and neurodegenerative disorders, AD, ALS | Lin et al., 2023; George and Geller, 2018; Rosmus et al., 2022; Vay et al., 2021; Rentsendorj et al., 2018 |
| 74 | Calprotectin ( S100A8/S100A9 (MRP8, MRP9) | Neutrophils and monocytes/macrophages | Protein, S100 family, leukocyte recruitment | Inflammatory diseases, trauma, stress, lung disorders, asthma, TBI | Shepherd et al., 2006; Yui et al., 2003; Kassianidis et al., 2022; Yang et al., 2021; Gruel et al., 2024 |
| 75 | VIP (vasoactive intestinal polypeptide) | Neurons, endocrine and immune cells, cells in the intestine, pituitary | Hormone, neurotransmitter, neuromodulator, anti-inflammatory, regulate astrocytes and microglia, neuroprotective, anti-apoptotic, antioxidant, reduce Aβ plaques in AD | Osteoarthritis, neurodegenerative disorders, AD, PD, neuroinflammation | Korkmaz et al., 2019; Korkmaz and Tuncel, 2018; Carniglia et al., 2017; Morell et al., 2012; Mosley et al., 2019 |
Neurovascular/BBB and neuroinflammatory markers.
The BBB is a crucial component of the NVU and plays an important role in the homeostasis of the brain. The NVU regulates BBB permeability, removal of toxic byproducts, and performs immune monitoring. BBB disruption and increased permeability are commonly observed in neurodegenerative disorders and neurotrauma, which increases BBB permeability causing or upregulating neuroinflammatory responses, neuroinflammation and neuronal loss (Yu et al., 2020). Therefore, we have highlighted recent advances in the study of BBB pathogenesis using the BBB-on-a-Chip model for CNS disorders and neurotherapeutics as briefly provided below.
BBB-on-a-Chip for CNS disorders and neurotherapeutics
The integrity of the BBB is maintained by astrocytes, pericytes, endothelial cells, and neurons, TJ, AdJ and GP proteins of the BBB. This integrity is crucial for normal brain function. However, chronic damage to NVU and BBB components leads to BBB dysfunction, increased BBB permeability/leakage, and neuroinflammation in many neurodegenerative diseases (Ohbuchi et al., 2024; Yoon et al., 2021). Therefore, the ability to model BBB behavior and pathogenesis is essential for the understanding of CNS disorders and neurotherapeutics. Vascularization in the brain organoids can be induced by modeling BBB micro environment using chip technology (Urrestizala-Arenaza et al., 2024). The BBB-on-a-chip (BBB chip) micro-engineered laboratory technology is a powerful in vitro model closely resembling human BBB structure to study normal and diseased states (Peng et al., 2022; Berjaoui et al., 2024). BBB-on-a-chip technology has significantly improved over the last decade and has been used to study various neurological diseases including AD, PD and Multiple Sclerosis (MS) (Berjaoui et al., 2024; Kawakita et al., 2022; Yoon et al., 2021; Palma-Florez et al., 2023). Recently neuroinflammation on-a-chip for studying MS (Berjaoui et al., 2024) and neuropathogenesis-on-chips (Amartumur et al., 2024) technology have been reported. The recently developed in vitro microfluidic/microfluidic human BBB-on-a-chip modeling using brain endothelial cells, pericytes, and astrocytes tri-culture model along with immune cell (T-cell) migration will be highly useful for understanding BBB functions, permeability, the pathogenesis of brain diseases, and evaluation of neurotherapeutic drugs that target the BBB (Ohbuchi et al., 2024). However, a fully efficient BBB-on-a-Chip model is still not available to date. A recent article described the use of built-in sensors to characterize BBB models via quasi-direct current and electrical impedance measurements, and various biosensors for the detection of metabolites, drugs, or toxic agents (Kincses et al., 2023). Microfluidic BBB-on-a-Chip provides an engineered physiological microenvironment necessary for real-time monitoring of barrier properties using human cells (Musafargani et al., 2020). The availability of AXION Maestro Edge multiwell microelectrode array (MEA) system (Axion BioSystems, Atlanta, GA) coupled with NETRI’s NeuroFluidics devices (NETRI, Lyon, France) could significantly enhance brain-on-a-Chip and BBB-on-a-Chip modeling in the study of brain disorders including neurotrauma/TBI, and development of drugs that target the BBB (Cohen et al., 2024; Ohbuchi et al., 2024). In a 3D microfluidic system, brain organoids are placed at the center chamber and endothelial cells and pericytes are placed on the side channels to create a micro vascularization system (Urrestizala-Arenaza et al., 2024) In a study, BBBs-on-chips were exposed to TNF-α and IL-1β to mimic neuroinflammation and studies the BBBs-on-chip’s barrier function, cell morphology, increased expression of cell adhesion molecules, increased permeability, and T cell adhesion, extravasation, and migration across BBB-on-chips (Nair et al., 2023). Even though brain-on-a-chip technology advanced the understanding of BBB pathophysiology, these models are still in a preliminary state, and the neurospheroids are still far from the human brain tissue. Thus, new and more advanced clinically relevant bioengineered models of human brain-on-a-chip for drug efficacy evaluation are required (Staicu et al., 2021; Cui and Cho, 2022). We are currently working on a BBB-on-a-Chip model to create disease-surrogate models for different brain disorders. Further research advancement in the BBB-on-a-Chip model could enhance the understanding of BBB dynamics in both health and disease conditions and assist in the development of treatments that target the BBB.
Conclusion
Neuroinflammation is a hallmark of many neurological disorders. Neuroinflammatory and neurodegenerative disorders are multifaceted processes involving the interaction of astrocytes, endothelial cells, neurons, microglia and infiltrating leukocytes as well as peripheral systems. Chronic release of neuroinflammatory mediators induces neuroinflammation, neurodegeneration, synaptic and neuronal loss and BBB dysfunction in the brain. Several molecules expressed by brain cells infiltrating peripheral leukocytes participate in the neuroinflammatory response in specific regions of the brain. Damage of NVU/BBB, TJ and AdJ proteins as well as neuroinflammatory markers could be assessed in the tissue as well as in CSF and blood though they are not specific to many brain disorders. Nevertheless, measuring such biomarkers is crucial for the diagnosis, severity assessment and treatment efficacy of various neurodegenerative disorders.
Statements
Author contributions
DK: Conceptualization, Writing – original draft, Writing – review and editing, Supervision. KD: Writing – review and editing. JC: Writing – review and editing. DV: Writing – review and editing. RJ: Writing – review and editing. SK: Writing – review and editing. TA: Writing – review and editing. BC: Writing – review and editing. AC: Writing – review and editing. NK: Writing – review and editing. TT: Writing – review and editing.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of the article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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References
1
AgarwalK.BacklerW.BayramE.BloomL.BoeveB. F.ChaJ. H.et al (2024). Lewy body dementia: Overcoming barriers and identifying solutions.Alzheimers Dement.202298–2308. 10.1002/alz.13674
2
AhmadS. J.FeigenC. M.VazquezJ. P.KobetsA. J.AltschulD. J. (2022). Neurological Sequelae of COVID-19.J. Integr. Neurosci.2177. 10.31083/j.jin2103077
3
AhmedM. E.SelvakumarG. P.KempurajD.RaikwarS. P.ThangavelR.BazleyK.et al (2020). Neuroinflammation mediated by GMF exacerbates neuronal injury in an in vitro model of traumatic brain injury.J. Neurotrauma371645–1655. 10.1089/neu.2019.6932
4
AksnesM.CapognaE.Vidal-PineiroD.ChaudhryF. A.MyrstadM.IdlandA. V.et al (2023). Matrix metalloproteinases are associated with brain atrophy in cognitively unimpaired individuals.Neurobiol. Aging13111–23. 10.1016/j.neurobiolaging.2023.05.012
5
Alarcon-MartinezL.YemisciM.DalkaraT. (2021). Pericyte morphology and function.Histol. Histopathol.36633–643. 10.14670/HH-18-314
6
AlbiniM.Krawczun-RygmaczewskaA.CescaF. (2023). Astrocytes and brain-derived neurotrophic factor (BDNF).Neurosci. Res.19742–51. 10.1016/j.neures.2023.02.001
7
AllenS. J.WatsonJ. J.ShoemarkD. K.BaruaN. U.PatelN. K. (2013). GDNF, NGF and BDNF as therapeutic options for neurodegeneration.Pharmacol. Ther.138155–175. 10.1016/j.pharmthera.2013.01.004
8
AlluriH.PeddaboinaC. S.TharakanB. (2024). Evaluation of Tight Junction Integrity in Brain Endothelial Cells Using Confocal Microscopy.Methods Mol. Biol.2711257–262. 10.1007/978-1-0716-3429-5_21
9
AlonsoA. D. C.El IdrissiA.CandiaR.MorozovaV.KleimanF. E. (2024). Tau: More than a microtubule-binding protein in neurons.Cytoskeleton8171–77. 10.1002/cm.21795
10
AlsbrookD. L.Di NapoliM.BhatiaK.BillerJ.AndalibS.HindujaA.et al (2023). Neuroinflammation in acute ischemic and hemorrhagic stroke.Curr. Neurol. Neurosci. Rep.23407–431. 10.1007/s11910-023-01282-2
11
Al-ThomaliA. W.Al-KuraishyH. M.Al-GareebA. I.De WaardM.SabatierJ. M.Khan KhalilA. A.et al (2022). Role of neuropilin 1 in COVID-19 patients with acute ischemic stroke.Biomedicines102032. 10.3390/biomedicines10082032
12
AmartumurS.NguyenH.HuynhT.KimT. S.WooR. S.OhE.et al (2024). Neuropathogenesis-on-chips for neurodegenerative diseases.Nat. Commun.152219. 10.1038/s41467-024-46554-8
13
Amini HarandiA.SiavoshiF.Shirzadeh BaroughS.Amini HarandiA.PakdamanH.SahraianM. A.et al (2022). Vascular endothelial growth factor as a predictive and prognostic biomarker for multiple sclerosis.Neuroimmunomodulation29476–485. 10.1159/000525600
14
AntipovaD.BandopadhyayR. (2017). Expression of DJ-1 in neurodegenerative disorders.Adv. Exp. Med. Biol.103725–43. 10.1007/978-981-10-6583-5_3
15
AsghariK.NiknamZ.Mohammadpour-AslS.ChodariL. (2024). Cellular junction dynamics and Alzheimer’s disease: a comprehensive review.Mol Biol Rep.51273. 10.1007/s11033-024-09242-w
16
Aydogan AvsarP.AkkusM. (2024). ZO-1 serum levels as a potential biomarker for psychotic disorder.Clin. Neuropharmacol.4767–71. 10.1097/WNF.0000000000000590
17
BabkinaA. S.LyubomudrovM. A.GolubevM. A.PisarevM. V.GolubevA. M. (2024). Neuron-specific enolase-what are we measuring?Int. J. Mol. Sci.255040. 10.3390/ijms25095040
18
BaneckiK.DoraK. A. (2023). Endothelin-1 in Health and Disease.Int. J. Mol. Sci.2411295. 10.3390/ijms241411295
19
BeiJ.Miranda-MoralesE. G.GanQ.QiuY.HusseinzadehS.LiewJ. Y.et al (2023). Circulating exosomes from Alzheimer’s Disease suppress vascular endothelial-cadherin expression and induce barrier dysfunction in recipient brain microvascular endothelial cell.J. Alzheimers Dis.95869–885. 10.3233/JAD-230347
20
BenvenisteE. N.NguyenV. T.WesemannD. R. (2004). Molecular regulation of CD40 gene expression in macrophages and microglia.Brain Behav. Immun.187–12. 10.1016/j.bbi.2003.09.001
21
BerjaouiC.KachouhC.JoumaaS.Hussein GhayyadM.Abate BekeleB.AjirenikeR.et al (2024). Neuroinflammation-on-a-chip for multiple sclerosis research: a narrative review.Ann. Med. Surg.864053–4059. 10.1097/MS9.0000000000002231
22
BhendM. E.KempurajD.SinhaN. R.GuptaS.MohanR. R. (2023). Role of aquaporins in corneal healing post chemical injury.Exp. Eye Res.228109390. 10.1016/j.exer.2023.109390
23
BhowmickS.D’MelloV.CarusoD.WallersteinA.Abdul-MuneerP. M. (2019). Impairment of pericyte-endothelium crosstalk leads to blood-brain barrier dysfunction following traumatic brain injury.Exp. Neurol.317260–270. 10.1016/j.expneurol.2019.03.014
24
BohnertS.WirthC.SchmitzW.TrellaS.MonoranuC. M.OndruschkaB.et al (2021). Myelin basic protein and neurofilament H in postmortem cerebrospinal fluid as surrogate markers of fatal traumatic brain injury.Int. J. Legal Med.1351525–1535. 10.1007/s00414-021-02606-y
25
BoulayA. C.MazeraudA.CisterninoS.SaubameaB.MaillyP.JourdrenL.et al (2015). Immune quiescence of the brain is set by astroglial connexin 43.J. Neurosci.354427–4439. 10.1523/JNEUROSCI.2575-14.2015
26
BoutteA. M.Deng-BryantY.JohnsonD.TortellaF. C.DaveJ. R.ShearD. A.et al (2016). Serum Glial Fibrillary Acidic Protein Predicts Tissue Glial Fibrillary Acidic Protein Break-Down Products and Therapeutic Efficacy after Penetrating Ballistic-Like Brain Injury.J. Neurotrauma33147–156. 10.1089/neu.2014.3672
27
BozoyanL.DumasA.PatenaudeA.VallieresL. (2015). Interleukin-36gamma is expressed by neutrophils and can activate microglia, but has no role in experimental autoimmune encephalomyelitis.J. Neuroinflammation12173. 10.1186/s12974-015-0392-7
28
BrettB. L.GardnerR. C.GodboutJ.Dams-O’ConnorK.KeeneC. D. (2022). Traumatic brain injury and risk of neurodegenerative disorder.Biol. Psychiatry91498–507. 10.1016/j.biopsych.2021.05.025
29
BrunoF.AbondioP.MontesantoA.LuiselliD.BruniA. C.MalettaR. (2023). The Nerve growth factor receptor (NGFR/p75(NTR)): a major player in Alzheimer’s disease.Int. J. Mol. Sci.24:3200. 10.3390/ijms24043200
30
BruntV. E.IkobaA. P.ZiembaB. P.BallakD. B.HoischenA.DinarelloC. A.et al (2023). Circulating interleukin-37 declines with aging in healthy humans: relations to healthspan indicators and IL37 gene SNPs.Geroscience4565–84. 10.1007/s11357-022-00587-3
31
BuneevaO.MedvedevA. (2024). Ubiquitin Carboxyl-Terminal Hydrolase L1 and Its Role in Parkinson’s Disease.Int. J. Mol. Sci.251303. 10.3390/ijms25021303
32
Cantuti-CastelvetriL.OjhaR.PedroL. D.DjannatianM.FranzJ.KuivanenS.et al (2020). Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity.Science370856–860. 10.1126/science.abd2985
33
CaoK.LiaoX.LuJ.YaoS.WuF.ZhuX.et al (2018). IL-33/ST2 plays a critical role in endothelial cell activation and microglia-mediated neuroinflammation modulation.J. Neuroinflammation15136. 10.1186/s12974-018-1169-6
34
CaoX.TabuchiK. (2017). Functions of synapse adhesion molecules neurexin/neuroligins and neurodevelopmental disorders.Neurosci. Res.1163–9. 10.1016/j.neures.2016.09.005
35
CarnigliaL.RamirezD.DurandD.SabaJ.TuratiJ.CarusoC.et al (2017). Neuropeptides and microglial activation in inflammation, pain, and neurodegenerative diseases.Mediators Inflamm.2017:5048616. 10.1155/2017/5048616
36
CattaneoM. (2015). P2Y12 receptors: structure and function.J. Thromb. Haemost.13 (Suppl. 1), S10–S16. 10.1111/jth.12952
37
ChahineL. M.SternM. B.Chen-PlotkinA. (2014). Blood-based biomarkers for Parkinson’s disease.Parkinsonism Relat. Disord.20S99–S103. 10.1016/S1353-8020(13)70025-7
38
Chase HuizarC.RaphaelI.ForsthuberT. G. (2020). Genomic, proteomic, and systems biology approaches in biomarker discovery for multiple sclerosis.Cell Immunol.358104219. 10.1016/j.cellimm.2020.104219
39
ChenY.WangY.XuJ.HouT.ZhuJ.JiangY.et al (2023). Multiplex assessment of serum chemokines CCL2, CCL5, CXCL1, CXCL10, and CXCL13 following traumatic brain injury.Inflammation.46244–255. 10.1007/s10753-022-01729-7
40
ChinE.GohE. (2018). Blood-brain barrier on a chip.Methods Cell Biol.146159–182. 10.1016/bs.mcb.2018.06.003
41
ChoS. J.ParkM. H.HanC.YoonK.KohY. H. (2017). VEGFR2 alteration in Alzheimer’s disease.Sci. Rep.717713. 10.1038/s41598-017-18042-1
42
ChuP. H.ChenS. C.ChenH. Y.WuC. B.HuangW. T.ChiangH. Y. (2023). Astrocyte-associated fibronectin promotes the proinflammatory phenotype of astrocytes through beta1 integrin activation.Mol. Cell Neurosci.125103848. 10.1016/j.mcn.2023.103848
43
CibelliA.StoutR.TimmermannA.de MenezesL.GuoP.MaassK.et al (2021). Cx43 carboxyl terminal domain determines AQP4 and Cx30 endfoot organization and blood brain barrier permeability.Sci. Rep.1124334. 10.1038/s41598-021-03694-x
44
Cintron-ColonA. F.Almeida-AlvesG.BoyntonA. M.SpitsbergenJ. M. (2020). GDNF synthesis, signaling, and retrograde transport in motor neurons.Cell Tissue Res.38247–56. 10.1007/s00441-020-03287-6
45
CohenJ.MathewA.DourvetakisK. D.Sanchez-GuerreroE.PangeniR. P.GurusamyN.et al (2024). Recent research trends in neuroinflammatory and neurodegenerative disorders.Cells13511. 10.3390/cells13060511
46
CraigA. M.KangY. (2007). Neurexin-neuroligin signaling in synapse development.Curr. Opin. Neurobiol.1743–52. 10.1016/j.conb.2007.01.011
47
CuiB.ChoS. W. (2022). Blood-brain barrier-on-a-chip for brain disease modeling and drug testing.BMB Rep.55213–219. 10.5483/BMBRep.2022.55.5.043
48
CuligL.ChuX.BohrV. A. (2022). Neurogenesis in aging and age-related neurodegenerative diseases.Ageing Res. Rev.78101636. 10.1016/j.arr.2022.101636
49
CustodiaA.Aramburu-NunezM.Rodriguez-ArrizabalagaM.Pias-PeleteiroJ. M.Vazquez-VazquezL.Camino-CastineirasJ.et al (2023). Biomarkers Assessing Endothelial Dysfunction in Alzheimer’s Disease.Cells12962. 10.3390/cells12060962
50
DaiW.ZhanM.GaoY.SunH.ZouY.LaurentR.et al (2024). Brain delivery of fibronectin through bioactive phosphorous dendrimers for Parkinson’s disease treatment via cooperative modulation of microglia.Bioact. Mater.3845–54. 10.1016/j.bioactmat.2024.04.005
51
DejanovicB.ShengM.HansonJ. E. (2024). Targeting synapse function and loss for treatment of neurodegenerative diseases.Nat. Rev. Drug Discov.2323–42. 10.1038/s41573-023-00823-1
52
DichevV.KazakovaM.SarafianV. (2020). YKL-40 and neuron-specific enolase in neurodegeneration and neuroinflammation.Rev. Neurosci.31539–553. 10.1515/revneuro-2019-0100
53
DingX. W.LiR.GeethaT.TaoY. X.BabuJ. R. (2020). Nerve growth factor in metabolic complications and Alzheimer’s disease: Physiology and therapeutic potential.Biochim. Biophys. Acta Mol. Basis Dis.1866165858. 10.1016/j.bbadis.2020.165858
54
DingZ. B.SongL. J.WangQ.KumarG.YanY. Q.MaC. G. (2021). Astrocytes: a double-edged sword in neurodegenerative diseases.Neural Regen. Res.161702–1710. 10.4103/1673-5374.306064
55
DithmerS.BlasigI. E.FraserP. A.QinZ.HaseloffR. F. (2024). The basic requirement of tight junction proteins in blood-brain barrier function and their role in pathologies.Int. J. Mol. Sci.255601. 10.3390/ijms25115601
56
DominguesA.FantinA. (2021). Neuropilin 1 regulation of vascular permeability signaling.Biomolecules11666. 10.3390/biom11050666
57
D’Orleans-JusteP.Akide NdungeO. B.DesbiensL.TanowitzH. B.DesruisseauxM. S. (2019). Endothelins in inflammatory neurological diseases.Pharmacol. Ther.194145–160. 10.1016/j.pharmthera.2018.10.001
58
DuanW.ZhangY. P.HouZ.HuangC.ZhuH.ZhangC. Q.et al (2016). Novel Insights into NeuN: from Neuronal Marker to Splicing Regulator.Mol. Neurobiol.531637–1647. 10.1007/s12035-015-9122-5
59
DulyA. M. P.KaoF. C. L.TeoW. S.KavallarisM. (2022). betaIII-tubulin gene regulation in health and disease.Front. Cell Dev. Biol.10:851542. 10.3389/fcell.2022.851542
60
EcheverriaV.BarretoG. E.Avila-RodriguezcM.TarasovV. V.AlievG. (2017). Is VEGF a Key Target of Cotinine and Other Potential Therapies Against Alzheimer Disease?Curr. Alzheimer. Res.141155–1163. 10.2174/1567205014666170329113007
61
ElahiF. M.CasalettoK. B.La JoieR.WaltersS. M.HarveyD.WolfA.et al (2020). Plasma biomarkers of astrocytic and neuronal dysfunction in early- and late-onset Alzheimer’s disease.Alzheimers Dement.16681–695. 10.1016/j.jalz.2019.09.004
62
ElkabesS.DiCicco-BloomE. M.BlackI. B. (1996). Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function.J. Neurosci.162508–2521. 10.1523/JNEUROSCI.16-08-02508.1996
63
ErenlerA. K.BaydinA. (2020). Interleukin-33 (IL-33) as a diagnostic and prognostic factor in traumatic brain injury.Emerg. Med. Int.20201832345. 10.1155/2020/1832345
64
FanJ.FongT.ChenX.ChenC.LuoP.XieH. (2018). Glia maturation factor-beta: a potential therapeutic target in neurodegeneration and neuroinflammation.Neuropsychiatr. Dis. Treat.14495–504. 10.2147/NDT.S157099
65
FordM. M.GeorgeB. E.Van LaarV. S.HolleranK. M.NaidooJ.HadaczekP.et al (2023). GDNF gene therapy for alcohol use disorder in male non-human primates.Nat. Med.292030–2040. 10.1038/s41591-023-02463-9
66
FuA. K.HungK. W.YuenM. Y.ZhouX.MakD. S.ChanI. C.et al (2016). IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline.Proc. Natl. Acad. Sci. U. S. A.113E2705–E2713. 10.1073/pnas.1604032113
67
FuscoF. R.PaldinoE. (2024). Is GDNF to Parkinson’s disease what BDNF is to Huntington’s disease?Neural Regen. Res.19973–974. 10.4103/1673-5374.385305
68
Gamez-ValeroA.BeyerK.BorrasF. E. (2019). Extracellular vesicles, new actors in the search for biomarkers of dementias.Neurobiol. Aging7415–20. 10.1016/j.neurobiolaging.2018.10.006
69
GaoQ.HernandesM. S. (2021). Sepsis-associated encephalopathy and blood-brain barrier dysfunction.Inflammation442143–2150. 10.1007/s10753-021-01501-3
70
GeisertE. E.Jr.JohnsonH. G.BinderL. I. (1990). Expression of microtubule-associated protein 2 by reactive astrocytes.Proc. Natl. Acad. Sci. U. S. A.873967–3971. 10.1073/pnas.87.10.3967
71
GeorgeN.GellerH. M. (2018). Extracellular matrix and traumatic brain injury.J. Neurosci. Res.96573–588. 10.1002/jnr.24151
72
GiovannoniF.QuintanaF. J. (2020). The Role of Astrocytes in CNS Inflammation.Trends Immunol.41805–819. 10.1016/j.it.2020.07.007
73
Gomez MorillasA.BessonV. C.LerouetD. (2021). Microglia and Neuroinflammation: What Place for P2RY12?Int. J. Mol. Sci.221636. 10.3390/ijms22041636
74
GranholmA. C.HamlettE. D. (2024). The Role of Tau Pathology in Alzheimer’s Disease and Down Syndrome.J. Clin. Med.131338. 10.3390/jcm13051338
75
GruelR.BijnensB.Van Den DaeleJ.ThysS.WillemsR.WuytsD.et al (2024). S100A8-enriched microglia populate the brain of tau-seeded and accelerated aging mice.Aging Cell.23e14120. 10.1111/acel.14120
76
GuoS.WangH.YinY. (2022). Microglia Polarization From M1 to M2 in Neurodegenerative Diseases.Front. Aging Neurosci.14:815347. 10.3389/fnagi.2022.815347
77
GuptaT.KumarM.KaurU. J.RaoA.BhartiR. (2024). Mapping ACE2 and TMPRSS2 co-expression in human brain tissue: implications for SARS-CoV-2 neurological manifestations.J. Neurovirol.10.1007/s13365-024-01206-x
78
Gusel’nikovaV. V.KorzhevskiyD. E. (2015). NeuN As a Neuronal Nuclear Antigen and Neuron Differentiation Marker.Acta Naturae.742–47.
79
HaffkeM.FreitagH.RudolfG.SeifertM.DoehnerW.ScherbakovN.et al (2022). Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS).J. Transl. Med.20138. 10.1186/s12967-022-03346-2
80
HaqueA.RayS. K.CoxA.BanikN. L. (2016). Neuron specific enolase: a promising therapeutic target in acute spinal cord injury.Metab. Brain Dis.31487–495. 10.1007/s11011-016-9801-6
81
HarrisR.MinersJ. S.AllenS.LoveS. (2018). VEGFR1 and VEGFR2 in Alzheimer’s Disease.J. Alzheimers Dis.61741–752. 10.3233/JAD-170745
82
HaruwakaK.IkegamiA.TachibanaY.OhnoN.KonishiH.HashimotoA.et al (2019). Dual microglia effects on blood brain barrier permeability induced by systemic inflammation.Nat. Commun.105816. 10.1038/s41467-019-13812-z
83
HashimotoY.GreeneC.MunnichA.CampbellM. (2023). The CLDN5 gene at the blood-brain barrier in health and disease.Fluids Barriers CNS.2022. 10.1186/s12987-023-00424-5
84
HausratT. J.RadwitzJ.LombinoF. L.BreidenP.KneusselM. (2021). Alpha- and beta-tubulin isotypes are differentially expressed during brain development.Dev. Neurobiol.81333–350. 10.1002/dneu.22745
85
HawksworthJ.FernandezE.GevaertK. (2022). A new generation of AD biomarkers: 2019 to 2021.Ageing Res. Rev.79101654. 10.1016/j.arr.2022.101654
86
HegenA.KoidlS.WeindelK.MarmeD.AugustinH. G.FiedlerU. (2004). Expression of angiopoietin-2 in endothelial cells is controlled by positive and negative regulatory promoter elements.Arterioscler. Thromb Vasc. Biol.241803–1809. 10.1161/01.ATV.0000140819.81839.0e
87
HellwigK.KvartsbergH.PorteliusE.AndreassonU.ObersteinT. J.LewczukP.et al (2015). Neurogranin and YKL-40: independent markers of synaptic degeneration and neuroinflammation in Alzheimer’s disease.Alzheimers Res. Ther.774. 10.1186/s13195-015-0161-y
88
HickmanS.IzzyS.SenP.MorsettL.ElK. J. (2018). Microglia in neurodegeneration.Nat. Neurosci.211359–1369.
89
HossainI.MarklundN.CzeiterE.HutchinsonP.BukiA. (2024). Blood biomarkers for traumatic brain injury: A narrative review of current evidence.Brain Spine.4102735. 10.1016/j.bas.2023.102735
90
HostenbachS.D’HaeseleerM.KooijmanR.De KeyserJ. (2016). The pathophysiological role of astrocytic endothelin-1.Prog. Neurobiol.14488–102. 10.1016/j.pneurobio.2016.04.009
91
HuX.GengP.ZhaoX.WangQ.LiuC.GuoC.et al (2023). The NG2-glia is a potential target to maintain the integrity of neurovascular unit after acute ischemic stroke.Neurobiol. Dis.180106076. 10.1016/j.nbd.2023.106076
92
HuangX.GuoM.ZhangY.XieJ.HuangR.ZuoZ.et al (2023). Microglial IL-1RA ameliorates brain injury after ischemic stroke by inhibiting astrocytic CXCL1-mediated neutrophil recruitment and microvessel occlusion.Glia711607–1625. 10.1002/glia.24359
93
HumesC.SicA.KnezevicN. N. (2024). Substance P’s Impact on Chronic Pain and Psychiatric Conditions-A Narrative Review.Int. J. Mol. Sci.255905. 10.3390/ijms25115905
94
Ikeshima-KataokaH. (2016). Neuroimmunological Implications of AQP4 in Astrocytes.Int. J. Mol. Sci.171306. 10.3390/ijms17081306
95
IyerM. R.KunosG. (2021). Therapeutic approaches targeting the neurotensin receptors.Expert. Opin. Ther. Pat.31361–386. 10.1080/13543776.2021.1866539
96
JacksonR. J.MeltzerJ. C.NguyenH.ComminsC.BennettR. E.HudryE.et al (2022). APOE4 derived from astrocytes leads to blood-brain barrier impairment.Brain.1453582–3593. 10.1093/brain/awab478
97
JainN.LewisC. A.UlrichJ. D.HoltzmanD. M. (2023). Chronic TREM2 activation exacerbates Abeta-associated tau seeding and spreading.J. Exp. Med.22020654. 10.1084/jem.20220654
98
JanelidzeS.MattssonN.StomrudE.LindbergO.PalmqvistS.ZetterbergH.et al (2018). CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease.Neurology91e867–e877. 10.1212/WNL.0000000000006082
99
JiaoM.LiX.ChenL.WangX.YuanB.LiuT.et al (2020). Neuroprotective effect of astrocyte-derived IL-33 in neonatal hypoxic-ischemic brain injury.J. Neuroinflammation.17251. 10.1186/s12974-020-01932-z
100
JohnsonG. V.JopeR. S. (1992). The role of microtubule-associated protein 2 (MAP-2) in neuronal growth, plasticity, and degeneration.J. Neurosci. Res.33505–512. 10.1002/jnr.490330402
101
JuR.ZhuangZ. W.ZhangJ.LanahanA. A.KyriakidesT.SessaW. C.et al (2014). Angiopoietin-2 secretion by endothelial cell exosomes: regulation by the phosphatidylinositol 3-kinase (PI3K)/Akt/endothelial nitric oxide synthase (eNOS) and syndecan-4/syntenin pathways.J. Biol. Chem.289510–519. 10.1074/jbc.M113.506899
102
KadkovaA.RadeckeJ.SorensenJ. B. (2019). The SNAP-25 Protein Family.Neuroscience42050–71. 10.1016/j.neuroscience.2018.09.020
103
KassianidisG.SiampanosA.PoulakouG.AdamisG.RaptiA.MilionisH.et al (2022). Calprotectin and imbalances between acute-phase mediators are associated with critical illness in COVID-19.Int. J. Mol. Sci.234894. 10.3390/ijms23094894
104
KawakitaS.MandalK.MouL.MecwanM. M.ZhuY.LiS.et al (2022). Organ-on-a-chip models of the blood-brain barrier: recent advances and future prospects.Small18e2201401. 10.1002/smll.202201401
105
KellerG. S.MedeirosE. B.Dos SantosM. L. C.LidioA. V.KucharskaE.BudniJ. (2023). COVID-19 and Brain Aging: What are the Implications of Immunosenescence?Curr. Aging Sci.1689–96. 10.2174/1874609816666221228103320
106
KempurajD.AenlleK. K.CohenJ.MathewA.IslerD.PangeniR. P.et al (2024). COVID-19 and Long COVID: disruption of the neurovascular unit, blood-brain barrier, and tight junctions.Neuroscientist30421–439. 10.1177/10738584231194927
107
KempurajD.AhmedM. E.SelvakumarG. P.ThangavelR.DhaliwalA. S.DubovaI.et al (2020a). Brain injury-mediated neuroinflammatory response and Alzheimer’s disease.Neuroscientist26134–155. 10.1177/1073858419848293
108
KempurajD.AhmedM. E.SelvakumarG. P.ThangavelR.RaikwarS. P.ZaheerS. A.et al (2020b). Psychological stress-induced immune response and risk of Alzheimer’s disease in veterans from operation enduring freedom and operation Iraqi freedom.Clin. Ther.42974–982. 10.1016/j.clinthera.2020.02.018
109
KempurajD.AhmedM. E.SelvakumarG. P.ThangavelR.RaikwarS. P.ZaheerS. A.et al (2021). Acute Traumatic Brain Injury-Induced Neuroinflammatory Response and Neurovascular Disorders in the Brain.Neurotox Res.39359–368. 10.1007/s12640-020-00288-9
110
KempurajD.MentorS.ThangavelR.AhmedM. E.SelvakumarG. P.RaikwarS. P.et al (2019). Mast Cells in Stress, Pain, Blood-Brain Barrier, Neuroinflammation and Alzheimer’s Disease.Front. Cell Neurosci.1354.
111
KempurajD.SelvakumarG. P.ThangavelR.AhmedM. E.ZaheerS.KumarK. K.et al (2018). Glia maturation factor and mast cell-dependent expression of inflammatory mediators and proteinase activated receptor-2 in neuroinflammation.J Alzheimers Dis.10.3233/JAD-180786[Epub ahead of print].
112
KempurajD.ThangavelR.NatteruP. A.SelvakumarG. P.SaeedD.ZahoorH.et al (2016). Neuroinflammation Induces Neurodegeneration.J. Neurol. Neurosurg. Spine.1:1003.
113
KempurajD.ThangavelR.SelvakumarG. P.ZaheerS.AhmedM. E.RaikwarS. P.et al (2017). Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration.Front. Cell Neurosci.11:216. 10.3389/fncel.2017.00216
114
KenkhuisB.SomarakisA.KleindouwelL. R. T.van Roon-MomW. M. C.HolltT.van der WeerdL. (2022). Co-expression patterns of microglia markers Iba1, TMEM119 and P2RY12 in Alzheimer’s disease.Neurobiol. Dis.167105684. 10.1016/j.nbd.2022.105684
115
KhalilM.TeunissenC. E.OttoM.PiehlF.SormaniM. P.GattringerT.et al (2018). Neurofilaments as biomarkers in neurological disorders.Nat. Rev. Neurol.14577–589. 10.1038/s41582-018-0058-z
116
KimD. S.KimG. W. (2024). Biofluid-based Biomarkers in Traumatic Brain Injury: A Narrative Review.Brain Neurorehabil.17e8. 10.12786/bn.2024.17.e8
117
KimJ. H.AfridiR.LeeW. H.SukK. (2020). Proteomic examination of the neuroglial secretome: lessons for the clinic.Expert. Rev. Proteomics17207–220. 10.1080/14789450.2020.1745069
118
KincsesA.VighJ. P.PetrovszkiD.ValkaiS.KocsisA. E.WalterF. R.et al (2023). The use of sensors in blood-brain barrier-on-a-chip devices: current practice and future directions.Biosensors13357. 10.3390/bios13030357
119
KitchenP.SalmanM. M.HalseyA. M.Clarke-BlandC.MacDonaldJ. A.IshidaH.et al (2020). Targeting aquaporin-4 subcellular localization to treat central nervous system edema.Cell181e19. 10.1016/j.cell.2020.03.037
120
KontsekovaS.PolcicovaK.TakacovaM.PastorekovaS. (2016). Endosialin: molecular and functional links to tumor angiogenesis.Neoplasma63183–192. 10.4149/202_15090N474
121
KorczynA. D.GrinbergL. T. (2024). Is Alzheimer disease a disease?Nat. Rev. Neurol.20245–251. 10.1038/s41582-024-00940-4
122
KorfJ. M.HonarpishehP.MohanE. C.BanerjeeA.Blasco-ConesaM. P.HonarpishehP.et al (2022). CD11b(high) B cells increase after stroke and regulate microglia.J. Immunol.209288–300. 10.4049/jimmunol.2100884
123
KorkmazO. T.AyH.AytanN.CarrerasI.KowallN. W.DedeogluA.et al (2019). Vasoactive intestinal peptide decreases beta-amyloid accumulation and prevents brain atrophy in the 5xFAD mouse model of Alzheimer’s disease.J. Mol. Neurosci.68389–396. 10.1007/s12031-018-1226-8
124
KorkmazO. T.TuncelN. (2018). Advantages of Vasoactive Intestinal Peptide for the Future Treatment of Parkinson’s Disease.Curr. Pharm. Des.244693–4701. 10.2174/1381612825666190111150953
125
KumarA.StoicaB. A.LoaneD. J.YangM.AbulwerdiG.KhanN.et al (2017). Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury.J. Neuroinflammation1447. 10.1186/s12974-017-0819-4
126
KwonH. S.KohS. H. (2020). Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes.Transl. Neurodegener.942. 10.1186/s40035-020-00221-2
127
KyriatzisG.KhrestchatiskyM.FerhatL.ChatzakiE. A. (2024). Neurotensin and Neurotensin Receptors in Stress-related Disorders: Pathophysiology & Novel Drug Targets.Curr. Neuropharmacol.22916–934. 10.2174/1570159X21666230803101629
128
LapshinaK. V.EkimovaI. V. (2024). Aquaporin-4 and Parkinson’s Disease.Int. J. Mol. Sci.25672. 10.3390/ijms25031672
129
Le ThucO.BlondeauN.NahonJ. L.RovereC. (2015). The complex contribution of chemokines to neuroinflammation: switching from beneficial to detrimental effects.Ann. N. Y. Acad. Sci.1351127–140. 10.1111/nyas.12855
130
LeeJ. S.SatoW.SonC. G. (2024). Brain-regional characteristics and neuroinflammation in ME/CFS patients from neuroimaging: A systematic review and meta-analysis.Autoimmun. Rev.23103484. 10.1016/j.autrev.2023.103484
131
LiW.ChenZ.ChinI.ChenZ.DaiH. (2018). The Role of VE-cadherin in Blood-brain Barrier Integrity Under Central Nervous System Pathological Conditions.Curr. Neuropharmacol.161375–1384. 10.2174/1570159X16666180222164809
132
LiX.YanB.DuJ.XuS.LiuL.PanC.et al (2022). Recent Advances in Progresses and Prospects of IL-37 in Central Nervous System Diseases.Brain Sci.12723. 10.3390/brainsci12060723
133
LiaoV.CornmanH. L.MaE.KwatraS. G. (2024). Prurigo nodularis: new insights into pathogenesis and novel therapeutics.Br. J. Dermatol.190798–810. 10.1093/bjd/ljae052
134
LimK. H.YangS.KimS. H.JooJ. Y. (2021). Identifying New COVID-19 Receptor Neuropilin-1 in Severe Alzheimer’s disease patients group brain using genome-wide association study approach.Front. Genet.12:741175. 10.3389/fgene.2021.741175
135
Lima GiacobboB.DoorduinJ.KleinH. C.DierckxR.BrombergE.de VriesE. F. J. (2019). Brain-derived neurotrophic factor in brain disorders: focus on neuroinflammation.Mol. Neurobiol.563295–3312. 10.1007/s12035-018-1283-6
136
LinE. Y.XiW.AggarwalN.ShinoharaM. L. (2023). Osteopontin (OPN)/SPP1: from its biochemistry to biological functions in the innate immune system and the central nervous system (CNS).Int. Immunol.35171–180. 10.1093/intimm/dxac060
137
Lind-Holm MogensenF.ScafidiA.PoliA.MichelucciA. (2023). PARK7/DJ-1 in microglia: implications in Parkinson’s disease and relevance as a therapeutic target.J. Neuroinflammation2095. 10.1186/s12974-023-02776-z
138
ListaS.HampelH. (2017). Synaptic degeneration and neurogranin in the pathophysiology of Alzheimer’s disease.Expert. Rev. Neurother.1747–57. 10.1080/14737175.2016.1204234
139
LiuF.LiH.HongX.LiuY.YuZ. (2024). Research progress of neuron-specific enolase in cognitive disorder: a mini review.Front. Hum. Neurosci.18:1392519. 10.3389/fnhum.2024.1392519
140
LonnemannN.HosseiniS.OhmM.GeffersR.HillerK.DinarelloC. A.et al (2022). IL-37 expression reduces acute and chronic neuroinflammation and rescues cognitive impairment in an Alzheimer’s disease mouse model.Elife1175889. 10.7554/eLife.75889
141
LotankarS.PrabhavalkarK. S.BhattL. K. (2017). Biomarkers for Parkinson’s Disease: Recent Advancement.Neurosci. Bull.33585–597. 10.1007/s12264-017-0183-5
142
MacFadyenJ. R.HaworthO.RoberstonD.HardieD.WebsterM. T.MorrisH. R.et al (2005). Endosialin (TEM1, CD248) is a marker of stromal fibroblasts and is not selectively expressed on tumour endothelium.FEBS Lett.5792569–2575. 10.1016/j.febslet.2005.03.071
143
MalhotraA. K.IdeK.SalaheenZ.MahoodQ.CunninghamJ.HutchisonJ.et al (2024). Acute fluid biomarkers for diagnosis and prognosis in children with mild traumatic brain injury: a systematic review.Mol. Diagn. Ther.28169–187. 10.1007/s40291-023-00685-8
144
MalhotraS.MirasM. C. M.PappollaA.MontalbanX.ComabellaM. (2023). Liquid biopsy in neurological diseases.Cells121911. 10.3390/cells12141911
145
MartinL.BouvetP.ChounlamountriN.WatrinC.BesanconR.PinatelD.et al (2021). VEGF counteracts amyloid-beta-induced synaptic dysfunction.Cell Rep.35109121. 10.1016/j.celrep.2021.109121
146
MaryA.MancusoR.HenekaM. T. (2024). Immune Activation in Alzheimer Disease.Annu. Rev. Immunol.42585–613. 10.1146/annurev-immunol-101921-035222
147
MashaghiA.MarmalidouA.TehraniM.GraceP. M.PothoulakisC.DanaR. (2016). Neuropeptide substance P and the immune response.Cell Mol. Life Sci.734249–4264. 10.1007/s00018-016-2293-z
148
MatteoliM. (2024). The role of microglial TREM2 in development: A path toward neurodegeneration?Glia721544–1554. 10.1002/glia.24574
149
MayerM. G.FischerT. (2024). Microglia at the blood brain barrier in health and disease.Front. Cell Neurosci.18:1360195. 10.3389/fncel.2024.1360195
150
McMahonP. J.PanczykowskiD. M.YueJ. K.PuccioA. M.InoueT.SoraniM. D.et al (2015). Measurement of the glial fibrillary acidic protein and its breakdown products GFAP-BDP biomarker for the detection of traumatic brain injury compared to computed tomography and magnetic resonance imaging.J. Neurotrauma32527–533. 10.1089/neu.2014.3635
151
MehtaR. I.MehtaR. I. (2023). The Vascular-Immune Hypothesis of Alzheimer’s Disease.Biomedicines11408. 10.3390/biomedicines11020408
152
MiZ.GrahamS. H. (2023). Role of UCHL1 in the pathogenesis of neurodegenerative diseases and brain injury.Ageing Res. Rev.86101856. 10.1016/j.arr.2023.101856
153
MichaelB. D.Bricio-MorenoL.SorensenE. W.MiyabeY.LianJ.SolomonT.et al (2020). Astrocyte- and Neuron-Derived CXCL1 drives neutrophil transmigration and blood-brain barrier permeability in viral encephalitis.Cell Rep.32108150. 10.1016/j.celrep.2020.108150
154
Mina-OsorioP.WinnickaB.O’ConorC.GrantC. L.VogelL. K.Rodriguez-PintoD.et al (2008). CD13 is a novel mediator of monocytic/endothelial cell adhesion.J. Leukoc. Biol.84448–459. 10.1189/jlb.1107802
155
MiraR. G.LiraM.CerpaW. (2021). Traumatic brain injury: mechanisms of glial response.Front. Physiol.12:740939. 10.3389/fphys.2021.740939
156
Morales-MedinaJ. C.DumontY.QuirionR. (2010). A possible role of neuropeptide Y in depression and stress.Brain Res.1314194–205. 10.1016/j.brainres.2009.09.077
157
MorellM.Souza-MoreiraL.Gonzalez-ReyE. (2012). VIP in neurological diseases: more than a neuropeptide.Endocr. Metab. Immune Disord. Drug Targets12323–332. 10.2174/187153012803832549
158
MorrisH. R.SpillantiniM. G.SueC. M.Williams-GrayC. H. (2024). The pathogenesis of Parkinson’s disease.Lancet403293–304. 10.1016/S0140-6736(23)01478-2
159
MosleyR. L.LuY.OlsonK. E.MachhiJ.YanW.NammingaK. L.et al (2019). A synthetic agonist to vasoactive intestinal peptide receptor-2 induces regulatory T cell neuroprotective activities in models of Parkinson’s disease.Front. Cell Neurosci.13:421. 10.3389/fncel.2019.00421
160
MullardA. (2023). NfL makes regulatory debut as neurodegenerative disease biomarker.Nat. Rev. Drug Discov.22431–434. 10.1038/d41573-023-00083-z
161
Munoz ParejaJ. C.de Rivero VaccariJ. P.ChavezM. M.KerriganM.PringleC.GuthrieK.et al (2024). Prognostic and diagnostic utility of serum biomarkers in pediatric traumatic brain injury.J. Neurotrauma41106–122. 10.1089/neu.2023.0039
162
MusafarganiS.MishraS.GulyasM.MahalakshmiP.ArchunanG.PadmanabhanP.et al (2020). Blood brain barrier: A tissue engineered microfluidic chip.J. Neurosci. Methods331108525. 10.1016/j.jneumeth.2019.108525
163
NabizadehF.ZafariR.Alzheimer’s, and disease Neuroimaging I. (2024). Progranulin and neuropathological features of Alzheimer’s disease: longitudinal study.Aging Clin. Exp. Res.3655. 10.1007/s40520-024-02715-9
164
NagatsuT.NakashimaA.IchinoseH.KobayashiK. (2019). Human tyrosine hydroxylase in Parkinson’s disease and in related disorders.J. Neural Transm.126397–409. 10.1007/s00702-018-1903-3
165
NagelhusE. A.OttersenO. P. (2013). Physiological roles of aquaporin-4 in brain.Physiol. Rev.931543–1562. 10.1152/physrev.00011.2013
166
NairA. L.GroenendijkL.OverdevestR.FowkeT. M.AnnidaR.MocellinO.et al (2023). Human BBB-on-a-chip reveals barrier disruption, endothelial inflammation, and T cell migration under neuroinflammatory conditions.Front. Mol. Neurosci.16:1250123. 10.3389/fnmol.2023.1250123
167
NegiS.KhuranaN.DuggalN. (2024). The misfolding mystery: alpha-synuclein and the pathogenesis of Parkinson’s disease.Neurochem. Int.177105760. 10.1016/j.neuint.2024.105760
168
NguyenA. D.MalmstromT. K.AggarwalG.MillerD. K.VellasB.MorleyJ. E. (2022). Serum neurofilament light levels are predictive of all-cause mortality in late middle-aged individuals.EBioMedicine.82104146. 10.1016/j.ebiom.2022.104146
169
NoorA.ZahidS. (2017). A review of the role of synaptosomal-associated protein 25 (SNAP-25) in neurological disorders.Int. J. Neurosci.127805–811. 10.1080/00207454.2016.1248240
170
NordenD. M.TrojanowskiP. J.VillanuevaE.NavarroE.GodboutJ. P. (2016). Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge.Glia64300–316. 10.1002/glia.22930
171
O’CallaghanJ. P.MillerD. B. (2019). Neuroinflammation disorders exacerbated by environmental stressors.Metabolism100S153951. 10.1016/j.metabol.2019.153951
172
OhbuchiM.ShibutaM.TetsukaK.Sasaki-IwaokaH.OishiM.ShimizuF.et al (2024). Modeling of Blood-Brain Barrier (BBB) dysfunction and immune cell migration using human BBB-on-a-chip for drug discovery research.Int. J. Mol. Sci.256496. 10.3390/ijms25126496
173
OkonkwoD. O.YueJ. K.PuccioA. M.PanczykowskiD. M.InoueT.McMahonP. J.et al (2013). GFAP-BDP as an acute diagnostic marker in traumatic brain injury: results from the prospective transforming research and clinical knowledge in traumatic brain injury study.J. Neurotrauma301490–1497. 10.1089/neu.2013.2883
174
Ollen-BittleN.RoseboroughA. D.WangW.WuJ. D.WhiteheadS. N. (2022). Mechanisms and Biomarker Potential of Extracellular Vesicles in Stroke.Biology111231. 10.3390/biology11081231
175
OtsH. D.TraczJ. A.VinokuroffK. E.MustoA. E. (2022). CD40-CD40L in Neurological Disease.Int. J. Mol. Sci.234115. 10.3390/ijms23084115
176
OwensC. D.Bonin PintoC.DetwilerS.OlayL.Pinaffi-LangleyA.MukliP.et al (2024). Neurovascular coupling impairment as a mechanism for cognitive deficits in COVID-19.Brain Commun.6fcae080. 10.1093/braincomms/fcae080
177
Palma-FlorezS.Lopez-CanosaA.Moralez-ZavalaF.CastanoO.KoganM. J.SamitierJ.et al (2023). BBB-on-a-chip with integrated micro-TEER for permeability evaluation of multi-functionalized gold nanorods against Alzheimer’s disease.J. Nanobiotechnology21115. 10.1186/s12951-023-01798-2
178
PapadopoulosM. C.VerkmanA. S. (2007). Aquaporin-4 and brain edema.Pediatr. Nephrol.22778–784. 10.1007/s00467-006-0411-0
179
PathakN.VimalS. K.TandonI.AgrawalL.HongyiC.BhattacharyyaS. (2022). Neurodegenerative disorders of alzheimer, parkinsonism, amyotrophic lateral sclerosis and multiple sclerosis: an early diagnostic approach for precision treatment.Metab. Brain Dis.3767–104. 10.1007/s11011-021-00800-w
180
PattenJ.WangK. (2021). Fibronectin in development and wound healing.Adv. Drug Deliv. Rev.170353–368. 10.1016/j.addr.2020.09.005
181
PengB.HaoS.TongZ.BaiH.PanS.LimK. L.et al (2022). Blood-brain barrier (BBB)-on-a-chip: a promising breakthrough in brain disease research.Lab. Chip.223579–3602. 10.1039/d2lc00305h
182
PocockJ.VasilopoulouF.SvenssonE.CoskerK. (2024). Microglia and TREM2.Neuropharmacology257110020. 10.1016/j.neuropharm.2024.110020
183
PraschbergerR.KuenenS.SchoovaertsN.KaempfN.SinghJ.JanssensJ.et al (2023). Neuronal identity defines alpha-synuclein and tau toxicity.Neuron111e11. 10.1016/j.neuron.2023.02.033
184
RamaniS.BerardJ. A.WalkerL. A. S. (2021). The relationship between neurofilament light chain and cognition in neurological disorders: A scoping review.J. Neurol. Sci.420117229. 10.1016/j.jns.2020.117229
185
RangarajuS.RazaS. A.LiN. X.BetarbetR.DammerE. B.DuongD.et al (2018). Differential Phagocytic Properties of CD45(low) Microglia and CD45(high) Brain Mononuclear Phagocytes-Activation and Age-Related Effects.Front. Immunol.9:405. 10.3389/fimmu.2018.00405
186
RaoX.HuaF.ZhangL.LinY.FangP.ChenS.et al (2022). Dual roles of interleukin-33 in cognitive function by regulating central nervous system inflammation.J. Transl. Med.20369. 10.1186/s12967-022-03570-w
187
RaufA.BadoniH.Abu-IzneidT.OlatundeA.RahmanM. M.PainuliS.et al (2022). Neuroinflammatory Markers: Key Indicators in the Pathology of Neurodegenerative Diseases.Molecules273194. 10.3390/molecules27103194
188
ReissnerC.RunkelF.MisslerM. (2013). Neurexins.Genome Biol.14213. 10.1186/gb-2013-14-9-213
189
RempeR. G.HartzA. M.BauerB. (2016). Matrix metalloproteinases in the brain and blood-brain barrier: versatile breakers and makers.J. Cereb. Blood Flow Metab.361481–14507. 10.1177/0271678X16655551
190
RentsendorjA.SheynJ.FuchsD. T.DaleyD.SalumbidesB. C.SchubloomH. E.et al (2018). A novel role for osteopontin in macrophage-mediated amyloid-beta clearance in Alzheimer’s models.Brain Behav. Immun.67163–180. 10.1016/j.bbi.2017.08.019
191
RepiciM.GiorginiF. (2019). DJ-1 in Parkinson’s disease: clinical insights and therapeutic perspectives.J. Clin. Med.8377. 10.3390/jcm8091377
192
Requena-OcanaN.Flores-LopezM.PapaseitE.Garcia-MarchenaN.RuizJ. J.Ortega-PinazoJ.et al (2022). Vascular endothelial growth factor as a potential biomarker of neuroinflammation and frontal cognitive impairment in patients with alcohol use disorder.Biomedicines.10947. 10.3390/biomedicines10050947
193
ReverchonF.de ConciniV.LarrigaldieV.BenmerzougS.BriaultS.TogbeD.et al (2020). Hippocampal interleukin-33 mediates neuroinflammation-induced cognitive impairments.J. Neuroinflammation17268. 10.1186/s12974-020-01939-6
194
RhoS. S.AndoK.FukuharaS. (2017). Dynamic regulation of vascular permeability by vascular endothelial cadherin-mediated endothelial cell-cell junctions.J. Nippon Med. Sch.84148–159. 10.1272/jnms.84.148
195
RigoY. R.BenvenuttiR.PortelaL. V.StrogulskiN. R. (2024). Neurogenic potential of NG2 in neurotrauma: a systematic review.Neural Regen. Res.192673–2683. 10.4103/NRR.NRR-D-23-01031
196
RobinsonC. R.ZhangH.DoughertyP. M. (2014). Astrocytes, but not microglia, are activated in oxaliplatin and bortezomib-induced peripheral neuropathy in the rat.Neuroscience.274308–317. 10.1016/j.neuroscience.2014.05.051
197
RoccoM. L.SoligoM.ManniL.AloeL. (2018). Nerve Growth Factor: Early Studies and Recent Clinical Trials.Curr. Neuropharmacol.161455–1465. 10.2174/1570159X16666180412092859
198
RochfortK. D.CumminsP. M. (2015). Cytokine-mediated dysregulation of zonula occludens-1 properties in human brain microvascular endothelium.Microvasc. Res.10048–53. 10.1016/j.mvr.2015.04.010
199
RosmusD. D.LangeC.LudwigF.AjamiB.WieghoferP. (2022). The Role of Osteopontin in Microglia Biology: Current Concepts and Future Perspectives.Biomedicines10840. 10.3390/biomedicines10040840
200
RothermundtM.PetersM.PrehnJ. H.AroltV. (2003). S100B in brain damage and neurodegeneration.Microsc. Res. Tech.60614–632. 10.1002/jemt.10303
201
RuanC.ElyamanW. (2022). A New Understanding of TMEM119 as a Marker of Microglia.Front. Cell Neurosci.16:902372. 10.3389/fncel.2022.902372
202
SafwatA.HelmyA.GuptaA. (2023). The Role of Substance P Within Traumatic Brain Injury and Implications for Therapy.J. Neurotrauma401567–1583. 10.1089/neu.2022.0510
203
SatohJ.KinoY.AsahinaN.TakitaniM.MiyoshiJ.IshidaT.et al (2016). TMEM119 marks a subset of microglia in the human brain.Neuropathology3639–49. 10.1111/neup.12235
204
SchieraG.Di LiegroC. M.SchiroG.SorbelloG.Di LiegroI. (2024). Involvement of Astrocytes in the Formation, Maintenance, and Function of the Blood-Brain Barrier.Cells13150. 10.3390/cells13020150
205
ScholzA.PlateK. H.ReissY. (2015). Angiopoietin-2: a multifaceted cytokine that functions in both angiogenesis and inflammation.Ann. N. Y. Acad. Sci.134745–51. 10.1111/nyas.12726
206
SelvakumarG. P.AhmedM. E.IyerS. S.ThangavelR.KempurajD.RaikwarS. P.et al (2020a). Absence of glia maturation factor protects from axonal injury and motor behavioral impairments after traumatic brain injury.Exp. Neurobiol.29230–248. 10.5607/en20017
207
SelvakumarG. P.AhmedM. E.ThangavelR.KempurajD.DubovaI.RaikwarS. P.et al (2020b). A role for glia maturation factor dependent activation of mast cells and microglia in MPTP induced dopamine loss and behavioural deficits in mice.Brain Behav. Immun.10.1016/j.bbi.2020.01.013[Epub ahead of print].
208
ShabaniF.FarasatA.MahdaviM.GheibiN. (2018). Calprotectin (S100A8/S100A9): a key protein between inflammation and cancer.Inflamm. Res.67801–812. 10.1007/s00011-018-1173-4
209
ShahidehpourR. K.HigdonR. E.CrawfordN. G.NeltnerJ. H.IghodaroE. T.PatelE.et al (2021). Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain.Neurobiol. Aging9919–27. 10.1016/j.neurobiolaging.2020.12.003
210
ShahimP.PhamD. L.van der MerweA. J.MooreB.ChouY. Y.LippaS. M.et al (2024). Serum NfL and GFAP as biomarkers of progressive neurodegeneration in TBI.Alzheimers Dement.204663–4676. 10.1002/alz.13898
211
ShahimP.PolitisA.van der MerweA.MooreB.ChouY. Y.PhamD. L.et al (2020). Neurofilament light as a biomarker in traumatic brain injury.Neurology.95e610–e622. 10.1212/WNL.0000000000009983
212
SharmaC.WooH.KimS. R. (2022). Addressing blood-brain barrier impairment in Alzheimer’s Disease.Biomedicines1040742. 10.3390/biomedicines10040742
213
ShendeP.DesaiD. (2020). Physiological and therapeutic roles of neuropeptide Y on biological functions.Adv. Exp. Med. Biol.123737–47. 10.1007/5584_2019_427
214
ShepherdC. E.GoyetteJ.UtterV.RahimiF.YangZ.GeczyC. L.et al (2006). Inflammatory S100A9 and S100A12 proteins in Alzheimer’s disease.Neurobiol. Aging271554–1563. 10.1016/j.neurobiolaging.2005.09.033
215
ShiQ.GutierrezR. A.BhatM. A. (2024). Microglia, Trem2, and Neurodegeneration.Neuroscientist10.1177/10738584241254118[Epub ahead of print].
216
ShiW.JiangD.RandoH.KhandujaS.LinZ.HazelK.et al (2023). Blood-brain barrier breakdown in COVID-19 ICU survivors: an MRI pilot study.NeuroImmune Pharm. Ther.2333–338. 10.1515/nipt-2023-0018
217
SilvestroS.RaffaeleI.QuartaroneA.MazzonE. (2024). Innovative insights into traumatic brain injuries: biomarkers and new pharmacological targets.Int. J. Mol. Sci.252372. 10.3390/ijms25042372
218
SimsS. K.Wilken-ResmanB.SmithC. J.MitchellA.McGonegalL.Sims-RobinsonC. (2022). Brain-derived neurotrophic factor and nerve growth factor therapeutics for brain injury: the current translational challenges in preclinical and clinical research.Neural Plast.20223889300. 10.1155/2022/3889300
219
SindiI. A.TannenbergR. K.DoddP. R. (2014). Role for the neurexin-neuroligin complex in Alzheimer’s disease.Neurobiol. Aging35746–756. 10.1016/j.neurobiolaging.2013.09.032
220
SongP.KraincD. (2024). Diverse functions of parkin in midbrain dopaminergic neurons.Mov. Disord.10.1002/mds.29890
221
StaicuC. E.JipaF.AxenteE.RaduM.RaduB. M.SimaF. (2021). Lab-on-a-Chip Platforms as Tools for Drug Screening in Neuropathologies Associated with Blood-Brain Barrier Alterations.Biomolecules11916. 10.3390/biom11060916
222
StogsdillJ. A.RamirezJ.LiuD.KimY. H.BaldwinK. T.EnustunE.et al (2017). Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis.Nature551192–197. 10.1038/nature24638
223
SuW.AloiM. S.GardenG. A. (2016). MicroRNAs mediating CNS inflammation: Small regulators with powerful potential.Brain Behav. Immun.521–8. 10.1016/j.bbi.2015.07.003
224
SudhofT. C. (2008). Neuroligins and neurexins link synaptic function to cognitive disease.Nature455903–911. 10.1038/nature07456
225
SunM.BakerT. L.WilsonC. T.BradyR. D.MychasiukR.YamakawaG. R.et al (2022). Treatment with vascular endothelial growth factor-A worsens cognitive recovery in a rat model of mild traumatic brain injury.Front. Mol. Neurosci.15:937350. 10.3389/fnmol.2022.937350
226
SunM.BakerT. L.WilsonC. T.BradyR. D.YamakawaG. R.WrightD. K.et al (2024). Treatment with the vascular endothelial growth factor-A antibody, bevacizumab, has sex-specific effects in a rat model of mild traumatic brain injury.J. Cereb. Blood Flow Metab.44542–555. 10.1177/0271678X231212377
227
SwansonM. E. V.MrkelaM.MurrayH. C.CaoM. C.TurnerC.CurtisM. A.et al (2023). Microglial CD68 and L-ferritin upregulation in response to phosphorylated-TDP-43 pathology in the amyotrophic lateral sclerosis brain.Acta Neuropathol. Commun.1169. 10.1186/s40478-023-01561-6
228
TachibanaK.HirayamaR.SatoN.HattoriK.KatoT.TakedaH.et al (2024). Association of Plasma Claudin-5 with Age and Alzheimer Disease.Int. J. Mol. Sci.251419. 10.3390/ijms25031419
229
TanY. J.SiowI.SaffariS. E.TingS. K. S.LiZ.KandiahN.et al (2023). Plasma Soluble ST2 levels are higher in neurodegenerative disorders and associated with poorer cognition.J. Alzheimers Dis.92573–580. 10.3233/JAD-221072
230
TaracanovaA.TsilioniI.ContiP.NorwitzE. R.LeemanS. E.TheoharidesT. C. (2018). Substance P and IL-33 administered together stimulate a marked secretion of IL-1beta from human mast cells, inhibited by methoxyluteolin.Proc. Natl. Acad. Sci. U. S. A.115E9381–E9390. 10.1073/pnas.1810133115
231
TarawnehR.KasperR. S.SanfordJ.PhuahC. L.HassenstabJ.CruchagaC. (2022). Vascular endothelial-cadherin as a marker of endothelial injury in preclinical Alzheimer disease.Ann. Clin. Transl. Neurol.91926–1940. 10.1002/acn3.51685
232
TeunissenC. E.VerberkI. M. W.ThijssenE. H.VermuntL.HanssonO.ZetterbergH.et al (2022). Blood-based biomarkers for Alzheimer’s disease: towards clinical implementation.Lancet Neurol.2166–77. 10.1016/S1474-4422(21)00361-6
233
ThangavelR.KaurH.DubovaI.SelvakumarG. P.AhmedM. E.RaikwarS. P.et al (2024). Parkinson’s disease dementia patients: expression of glia maturation factor in the brain.Int. J. Mol. Sci.251182. 10.3390/ijms25021182
234
ThangavelR.KempurajD.ZaheerS.RaikwarS.AhmedM. E.SelvakumarG. P.et al (2017). Glia Maturation factor and mitochondrial uncoupling proteins 2 and 4 expression in the temporal cortex of Alzheimer’s disease brain.Front. Aging Neurosci.9:150. 10.3389/fnagi.2017.00150
235
ThangavelR.StolmeierD.YangX.AnantharamP.ZaheerA. (2012). Expression of glia maturation factor in neuropathological lesions of Alzheimer’s disease.Neuropathol. Appl. Neurobiol.38572–581. 10.1111/j.1365-2990.2011.01232.x
236
TheofilisP.SagrisM.OikonomouE.AntonopoulosA. S.SiasosG.TsioufisC.et al (2021). Inflammatory mechanisms contributing to endothelial dysfunction.Biomedicines970781. 10.3390/biomedicines9070781
237
TheoharidesT. C.KempurajD. (2023). Role of SARS-CoV-2 spike-protein-induced activation of microglia and mast cells in the pathogenesis of neuro-COVID.Cells12688. 10.3390/cells12050688
238
TheoharidesT. C.StewartJ. M.PanagiotidouS.MelamedI. (2016). Mast cells, brain inflammation and autism.Eur. J. Pharmacol.77896–102. 10.1016/j.ejphar.2015.03.086
239
ThorsellA. (2010). Brain neuropeptide Y and corticotropin-releasing hormone in mediating stress and anxiety.Exp. Biol. Med.2351163–1167. 10.1258/ebm.2010.009331
240
TogawaN.AyakiT.YoshiiD.MakiT.SawamotoN.TakahashiR. (2024). TMEM119-positive microglia were increased in the brains of patients with amyotrophic lateral sclerosis.Neurosci. Lett.833137829. 10.1016/j.neulet.2024.137829
241
TogoT.AkiyamaH.KondoH.IkedaK.KatoM.IsekiE.et al (2000). Expression of CD40 in the brain of Alzheimer’s disease and other neurological diseases.Brain Res.885117–121. 10.1016/s0006-8993(00)02984-x
242
TomkowiczB.RybinskiK.SebeckD.SassP.NicolaidesN. C.GrassoL.et al (2010). Endosialin/TEM-1/CD248 regulates pericyte proliferation through PDGF receptor signaling.Cancer Biol Ther.9908–915. 10.4161/cbt.9.11.11731
243
TranV. T. A.LeeL. P.ChoH. (2022). Neuroinflammation in neurodegeneration via microbial infections.Front. Immunol.13:907804. 10.3389/fimmu.2022.907804
244
TsilioniI.PantazopoulosH.ContiP.LeemanS. E.TheoharidesT. C. (2020). IL-38 inhibits microglial inflammatory mediators and is decreased in amygdala of children with autism spectrum disorder.Proc. Natl. Acad. Sci. U. S. A.11716475–16480. 10.1073/pnas.2004666117
245
TsilioniI.PatelA. B.PantazopoulosH.BerrettaS.ContiP.LeemanS. E.et al (2019). IL-37 is increased in brains of children with autism spectrum disorder and inhibits human microglia stimulated by neurotensin.Proc. Natl. Acad. Sci. U. S. A.11621659–21665. 10.1073/pnas.1906817116
246
TyagiK.RaiP.GautamA.KaurH.KapoorS.SutteeA.et al (2023). Neurological manifestations of SARS-CoV-2: complexity, mechanism and associated disorders.Eur. J. Med. Res.28307. 10.1186/s40001-023-01293-2
247
TziolosN. R.IoannouP.BaliouS.KofteridisD. P. (2023). Long COVID-19 Pathophysiology: What Do We Know So Far?Microorganisms1102458. 10.3390/microorganisms11102458
248
Urrestizala-ArenazaN.CerchioS.CavaliereF.MagliaroC. (2024). Limitations of human brain organoids to study neurodegenerative diseases: a manual to survive.Front. Cell Neurosci.18:1419526. 10.3389/fncel.2024.1419526
249
VafadariB.SalamianA.KaczmarekL. (2016). MMP-9 in translation: from molecule to brain physiology, pathology, and therapy.J. Neurochem.13991–114. 10.1111/jnc.13415
250
VainchteinI. D.ChinG.ChoF. S.KelleyK. W.MillerJ. G.ChienE. C.et al (2018). Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development.Science3591269–1273. 10.1126/science.aal3589
251
van de VeerdonkF. L.de GraafD. M.JoostenL. A.DinarelloC. A. (2018). Biology of IL-38 and its role in disease.Immunol. Rev.281191–196. 10.1111/imr.12612
252
Van Der NaaltJ. (2015). Resting functional imaging tools (MRS, SPECT, PET and PCT).Handb. Clin. Neurol.127295–308. 10.1016/B978-0-444-52892-6.00019-2
253
Van HulleC.InceS.OkonkwoO. C.BendlinB. B.JohnsonS. C.CarlssonC. M.et al (2024). Elevated CSF angiopoietin-2 correlates with blood-brain barrier leakiness and markers of neuronal injury in early Alzheimer’s disease.Transl. Psychiatry143. 10.1038/s41398-023-02706-w
254
VaresiA.CarraraA.PiresV. G.FlorisV.PierellaE.SavioliG.et al (2022). Blood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview.Cells111081367. 10.3390/cells11081367
255
Varillas-DelgadoD.Jimenez-AntonaC.Lizcano-AlvarezA.Cano-de-la-CuerdaR.Molero-SanchezA.Laguarta-ValS. (2023). Predictive Factors and ACE-2 Gene Polymorphisms in Susceptibility to Long COVID-19 Syndrome.Int. J. Mol. Sci.2416717. 10.3390/ijms242316717
256
VayS. U.OlschewskiD. N.PetereitH.LangeF.NazarzadehN.GrossE.et al (2021). Osteopontin regulates proliferation, migration, and survival of astrocytes depending on their activation phenotype.J. Neurosci. Res.992822–2843. 10.1002/jnr.24954
257
WakabayashiK.TanjiK.OdagiriS.MikiY.MoriF.TakahashiH. (2013). The Lewy body in Parkinson’s disease and related neurodegenerative disorders.Mol. Neurobiol.47495–508. 10.1007/s12035-012-8280-y
258
WakayamaE.KuzuT.TachibanaK.HirayamaR.OkadaY.KondohM. (2022). Modifying the blood-brain barrier by targeting claudin-5: Safety and risks.Ann. N. Y. Acad. Sci.151462–69. 10.1111/nyas.14787
259
WallerR.BaxterL.FillinghamD. J.CoelhoS.PozoJ. M.MozumderM.et al (2019). Iba-1-/CD68+ microglia are a prominent feature of age-associated deep subcortical white matter lesions.PLoS One14:e0210888. 10.1371/journal.pone.0210888
260
WangA.HeB. P. (2009). Characteristics and functions of NG2 cells in normal brain and neuropathology.Neurol. Res.31144–150. 10.1179/174313209X393555
261
WangK. K.Munoz ParejaJ. C.MondelloS.Diaz-ArrastiaR.WellingtonC.KenneyK.et al (2021a). Blood-based traumatic brain injury biomarkers - Clinical utilities and regulatory pathways in the United States, Europe and Canada.Expert. Rev. Mol. Diagn.211303–1321. 10.1080/14737159.2021.2005583
262
WangX. M.ZengP.FangY. Y.ZhangT.TianQ. (2021b). Progranulin in neurodegenerative dementia.J. Neurochem.158119–137. 10.1111/jnc.15378
263
WasikN.SokolB.HolyszM.MankoW.JuszkatR.JagodzinskiP. P.et al (2020). Serum myelin basic protein as a marker of brain injury in aneurysmal subarachnoid haemorrhage.Acta Neurochir.162545–552. 10.1007/s00701-019-04185-9
264
WeiS. S.ChenL.YangF. Y.WangS. Q.WangP. (2023a). The role of fibronectin in multiple sclerosis and the effect of drug delivery across the blood-brain barrier.Neural Regen. Res.182147–2155. 10.4103/1673-5374.369102
265
WeiZ. D.LiangK.ShettyA. K. (2023b). Complications of COVID-19 on the Central Nervous System: Mechanisms and Potential Treatment for Easing Long COVID.Aging Dis.141492–1510. 10.14336/AD.2023.0312
266
WicherG.WallenquistU.LeiY.EnokssonM.LiX.FuchsB.et al (2017). Interleukin-33 Promotes Recruitment of Microglia/Macrophages in Response to Traumatic Brain Injury.J. Neurotrauma.343173–3182. 10.1089/neu.2016.4900
267
WirthK. J.ScheibenbogenC.PaulF. (2021). An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.J. Transl. Med.19471. 10.1186/s12967-021-03143-3
268
WoltersF. J.BoenderJ.de VriesP. S.SonneveldM. A.KoudstaalP. J.de MaatM. P.et al (2018). Von Willebrand factor and ADAMTS13 activity in relation to risk of dementia: a population-based study.Sci. Rep.85474. 10.1038/s41598-018-23865-7
269
WoollacottI. O. C.ToomeyC. E.StrandC.CourtneyR.BensonB. C.RohrerJ. D.et al (2020). Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration.J. Neuroinflammation17234. 10.1186/s12974-020-01907-0
270
WysokinskiA. (2016). Serum levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) in depressed patients with schizophrenia.Nord. J. Psychiatry70267–271. 10.3109/08039488.2015.1087592
271
XiaP.JiX.YanL.LianS.ChenZ.LuoY. (2024). Roles of S100A8, S100A9 and S100A12 in infection, inflammation and immunity.Immunology171365–376. 10.1111/imm.13722
272
XiangY.XinJ.LeW.YangY. (2020). Neurogranin: A Potential Biomarker of Neurological and Mental Diseases.Front. Aging Neurosci.12:584743. 10.3389/fnagi.2020.584743
273
XieD.MiaoW.XuF.YuanC.LiS.WangC.et al (2022). IL-33/ST2 Axis protects against traumatic brain injury through enhancing the function of regulatory T Cells.Front. Immunol.13:860772. 10.3389/fimmu.2022.860772
274
XiongZ.ThangavelR.KempurajD.YangE.ZaheerS.ZaheerA. (2014). Alzheimer’s Disease: Evidence for the Expression of Interleukin-33 and Its Receptor ST2 in the Brain.J. Alzheimers Dis.10.3233/JAD-132081[Epub ahead of print].
275
XuW. D.HuangA. F. (2018). Role of Interleukin-38 in Chronic Inflammatory Diseases: A Comprehensive Review.Fron. Immunol.9:1462. 10.3389/fimmu.2018.01462
276
YadollahikhalesG.RojasJ. C. (2023). Anti-Amyloid Immunotherapies for Alzheimer’s Disease: A 2023 Clinical Update.Neurotherapeutics20914–931. 10.1007/s13311-023-01405-0
277
YamaguchiM.NakaoS.ArimaM.LittleK.SinghA.WadaI.et al (2024). Heterotypic macrophages/microglia differentially contribute to retinal ischaemia and neovascularisation.Diabetologia10.1007/s00125-024-06215-3
278
YangC.HuangX.HuangX.MaiH.LiJ.JiangT.et al (2016). Aquaporin-4 and Alzheimer’s Disease.J. Alzheimers Dis.52391–402. 10.3233/JAD-150949
279
YangC.ZhengC.ZhuangY.XuS.LiJ.HuC. (2024). Synaptic Vesicle-Related Proteins and Ubiquilin 2 in Cortical Synaptosomes Mediate Cognitive Impairment in Vascular Dementia Rats.Mol. Neurobiol.10.1007/s12035-024-04327-w
280
YangY.ShenL.XuM.ChenL.LuW.WangW. (2021). Serum calprotectin as a prognostic predictor in severe traumatic brain injury.Clin. Chim. Acta520101–107. 10.1016/j.cca.2021.06.009
281
YeungD.ManiasJ. L.StewartD. J.NagS. (2008). Decreased junctional adhesion molecule-A expression during blood-brain barrier breakdown.Acta Neuropathol.115635–642. 10.1007/s00401-008-0364-4
282
YongH. Y. F.RawjiK. S.GhorbaniS.XueM.YongV. W. (2019). The benefits of neuroinflammation for the repair of the injured central nervous system.Cell Mol. Immunol.16540–546. 10.1038/s41423-019-0223-3
283
YoonJ. K.KimJ.ShahZ.AwasthiA.MahajanA.KimY. (2021). Advanced Human BBB-on-a-Chip: A New Platform for Alzheimer’s Disease Studies.Adv. Healthc. Mater.10e2002285. 10.1002/adhm.202002285
284
YuX.JiC.ShaoA. (2020). Neurovascular Unit Dysfunction and Neurodegenerative Disorders.Front. Neurosci.14:334. 10.3389/fnins.2020.00334
285
YuiS.NakataniY.MikamiM. (2003). Calprotectin (S100A8/S100A9), an inflammatory protein complex from neutrophils with a broad apoptosis-inducing activity.Biol. Pharm. Bull.26753–760. 10.1248/bpb.26.753
286
Zapata-AcevedoJ. F.Mantilla-GalindoA.Vargas-SanchezK.Gonzalez-ReyesR. E. (2024). Blood-brain barrier biomarkers.Adv. Clin. Chem.1211–88. 10.1016/bs.acc.2024.04.004
287
Zare RafieM.EsmaeilzadehA.GhoreishiA.TahmasebiS.FaghihzadehE.ElahiR. (2021). IL-38 as an early predictor of the ischemic stroke prognosis.Cytokine146155626. 10.1016/j.cyto.2021.155626
288
ZetterbergH.BlennowK. (2016). Fluid biomarkers for mild traumatic brain injury and related conditions.Nat. Rev. Neurol.12563–574. 10.1038/nrneurol.2016.127
289
ZhangF.PanL.LianC.XuZ.ChenH.LaiW.et al (2024). ICAM-1 may promote the loss of dopaminergic neurons by regulating inflammation in MPTP-induced Parkinson’s disease mouse models.Brain Res. Bull.214110989. 10.1016/j.brainresbull.2024.110989
290
ZhangR.JiangH.LiuY.HeG. (2023). Structure, function, and pathology of Neurexin-3.Genes Dis.101908–1919. 10.1016/j.gendis.2022.04.008
291
ZhangS. R.NoldM. F.TangS. C.BuiC. B.NoldC. A.ArumugamT. V.et al (2019). IL-37 increases in patients after ischemic stroke and protects from inflammatory brain injury, motor impairment and lung infection in mice.Sci. Rep.96922. 10.1038/s41598-019-43364-7
292
ZhangX.WangL. P.ZioberA.ZhangP. J.BaggA. (2021). Ionized Calcium Binding Adaptor Molecule 1 (IBA1).Am. J. Clin. Pathol.15686–99. 10.1093/ajcp/aqaa209
293
ZhangZ.LiX.ZhouH.ZhouJ. (2022). NG2-glia crosstalk with microglia in health and disease.CNS Neurosci. Ther.281663–1674. 10.1111/cns.13948
294
ZhouL.TodorovicV. (2021). Interleukin-36: Structure, Signaling and Function.Adv. Exp. Med. Biol.21191–210. 10.1007/5584_2020_488
295
ZhouX.ShiQ.ZhangX.GuL.LiJ.QuanS.et al (2023). ApoE4-mediated blood-brain barrier damage in Alzheimer’s disease: Progress and prospects.Brain Res. Bull.199110670. 10.1016/j.brainresbull.2023.110670
296
ZhouY.CaiG.WangY.GuoY.YangZ.WangA.et al (2024). Microarray Chip-Based High-Throughput Screening of Neurofilament Light Chain Self-Assembling Peptide for Noninvasive Monitoring of Alzheimer’s Disease.ACS Nano.1818160–18175. 10.1021/acsnano.3c09642
297
ZingaropoliM. A.IannettaM.PiermatteoL.PasculliP.LatronicoT.MazzutiL.et al (2022). Neuro-Axonal Damage and Alteration of Blood-Brain Barrier Integrity in COVID-19 Patients.Cells112480. 10.3390/cells11162480
298
ZuccatoC.CattaneoE. (2009). Brain-derived neurotrophic factor in neurodegenerative diseases.Nat. Rev. Neurol.5311–322. 10.1038/nrneurol.2009.54
Summary
Keywords
blood-brain barrier disruption, glial cells, neuroinflammatory biomarkers, neurodegenerative disorders, neurofilament light, neurovascular unit, tight junction proteins
Citation
Kempuraj D, Dourvetakis KD, Cohen J, Valladares DS, Joshi RS, Kothuru SP, Anderson T, Chinnappan B, Cheema AK, Klimas NG and Theoharides TC (2024) Neurovascular unit, neuroinflammation and neurodegeneration markers in brain disorders. Front. Cell. Neurosci. 18:1491952. doi: 10.3389/fncel.2024.1491952
Received
05 September 2024
Accepted
07 October 2024
Published
25 October 2024
Volume
18 - 2024
Edited by
Arumugam R. Jayakumar, University of Miami, United States
Reviewed by
Krishnapriya Thangaretnam, University of Miami, United States
Kumar Vaibhav, Augusta University, United States
Suresh Babu Rangasamy, University of Illinois Chicago, United States
Updates
Copyright
© 2024 Kempuraj, Dourvetakis, Cohen, Valladares, Joshi, Kothuru, Anderson, Chinnappan, Cheema, Klimas and Theoharides.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Duraisamy Kempuraj, kduraisa@nova.edu; orcid.org/0000-0003-1148-8681
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