Edited by: Malstrokegorzata Kujawska, Poznan University of Medical Sciences, Poland
Reviewed by: Souvarish Sarkar, Brigham and Women’s Hospital and Harvard Medical School, United States; Tibor Rohacs, Rutgers New Jersey Medical School, United States
†These authors have contributed equally to this work and share first authorship
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Microglia are increasingly recognized as vital players in the pathology of a variety of neurodegenerative conditions including Alzheimer’s (AD) and Parkinson’s (PD) disease. While microglia have a protective role in the brain, their dysfunction can lead to neuroinflammation and contributes to disease progression. Also, a growing body of literature highlights the seven phosphoinositides, or PIPs, as key players in the regulation of microglial-mediated neuroinflammation. These small signaling lipids are phosphorylated derivates of phosphatidylinositol, are enriched in the brain, and have well-established roles in both homeostasis and disease.Disrupted PIP levels and signaling has been detected in a variety of dementias. Moreover, many known AD disease modifiers identified
Fifty million people worldwide currently present with neurodegenerative conditions, with 60–70% of these suffering from Alzheimer’s disease (AD) (World Alzheimer Report,
During development, microglia have key roles in shaping neuronal networks and modulating both the number of synapses and the strength of synaptic transmission (Colonna and Butovsky,
Phosphoinositides (PIPs), in brief, are acidic membrane lipids derived from phosphatidylinositol. These lipids, known to support key cellular functions in the brain, are increasingly recognized as important in neurodegenerative processes and microglial function (Raghu et al.,
This review aims to summarize the role of microglia in a variety of neurodegenerative conditions, as well as known phosphoinositide disturbances within these conditions. This will be followed by discussions on how alterations in phosphoinositides and their regulatory enzymes could affect specific microglial functions and thereby contribute to disease progression. Finally, for each microglial function discussed, we will explore how phosphoinositide-modifying therapies could potentially be used to ameliorate disease phenotypes.
AD, first characterized by Alois Alzheimer in 1907 (Alzheimer et al.,
Within AD, we know that 58–79% of sporadic cases are linked to the patient’s genes (Gatz et al.,
Nitric oxide (NO) curative therapy currently exists for the treatment of AD (Weller and Budson,
Parkinson’s disease (PD), first described by James Parkinson in 1817 (Parkinson,
Symptoms arise following the degeneration of dopaminergic neurons in the substantia nigra, which produce the neurotransmitter dopamine. Neuronal loss occurs following the formation of intraneuronal “Lewy bodies” which consist of aggregated bundles of misfolded α-synuclein (Lecours et al.,
Within the PD brain, microglia are thought to lose beneficial, whilst gaining detrimental, functions (Lecours et al.,
3, 4-dihydroxy-L-phenylalanine, the precursor to dopamine, acts as the “gold standard” PD treatment. Nevertheless, while this drug ameliorates many PD-associated motor defects, long-term use often results in debilitating dyskinesia and other motor fluctuations (Lane,
Microglia have also been implicated in the pathology of Huntington’s disease (HD; Yang H.-M. et al.,
PET studies on human HD post-mortem brains have demonstrated increased activation of microglia in HD compared with controls (Pavese et al.,
Amyotrophic lateral sclerosis (ALS) is a degenerative disease primarily characterized by muscle weakness and wasting, with 10–15% of patients also suffering from frontotemporal dementia (FTD). FTD results in progressive degeneration of frontal and anterior temporal lobes, with patients experiencing behavioral changes alongside impairments in executive functioning and, often, language. ALS is familial in 15% of cases, where it is caused by changes in one of more than 20 currently identified genes (Masrori and Van Damme,
As with other dementias, the role of microglia in ALS appears to be highly complex. C9orf72 knock-out mice, while showing no motor-neuron degeneration, show altered immune responses in microglia and macrophages, highlighting the importance of these myeloid cells in ALS pathogenesis (O’Rourke et al.,
Neurodegenerative conditions pose serious health and economic costs to our society. If left unchecked, cases are expected to triple by 2050 (Prince et al.,
Phosphoinositides are signaling lipids derived from phosphatidylinositol, which is comprised of diacylglycerol (DAG) moiety linked to a D-myo-inositol ring
Structure, metabolism, and location of phosphatidylinositides (PIPs) within mammalian cells.
Known functions of phosphoinositide (PIP) species within the brain and roles in neurodegeneration.
PIP species | Known functions in the brain | Roles in neurodegenerative disease | References |
---|---|---|---|
PI(3)P | Key regulator of endocytic trafficking, fusion, and autophagy. |
Inhibiting PIP-4 kinase (phosphorylates PI(3)P) reduces mHTT and rescues neurodegeneration in HD drosophila. |
Heras-Sandoval et al. ( |
PI(4)P | Potential roles in myelin formation. |
Pathophysiological concentrations of Aβ inhibit PI4K (generates PI(4)P) activity, both |
Stokes and Hawthorne ( |
PI(5)P | Roles in AKT/mTOR signaling, autophagy, and apoptosis. |
Inhibiting PIP-4 kinase [phosphorylates PI(5)P] reduces mHTT and rescues neurodegeneration in HD drosophila. | Boal et al. ( |
PI(3,4)P2 | Involved in the maturation of late-stage clathrin-coated pits and fast endophilin-mediated endocytosis. |
Mutations in the PI(3,4)P2 synthesis enzyme INPP5D increase genetic AD risk. |
Lambert et al. ( |
PI(4,5)P2 | Electrical signaling at the plasma membrane (including neurons). |
A genetic variant in PLCγ2, which breaks down PI(4,5)P2, protects against AD. |
Wallace and Claro ( |
PI(3,5)P2 | Regulates membrane trafficking, endocytic vesicle fission/fusion, organelle pH, intracellular ion channel function. |
The PI(3,5)P2 synthesis enzyme FIG4 acts as a risk factor for ALS. | Chow et al. ( |
PI(3,4,5)P3 | Regulates neurotransmitter release. |
Excess PI3K [generates PI(3,4,5)P3] activity in AD, reduced activity in PD. |
Bernier et al. ( |
Perhaps unsurprisingly given their key roles in the brain, PIPs have been implicated in a wide variety of dementia’s, including AD, PD, HD, and ALS. Precise perturbances of PIP species and their suspected effects on neurodegenerative disease are later discussed and summarized in
Growing evidence suggests that phosphoinositide dyshomeostasis plays a role in the development of a variety of dementias. Phosphoinositides, which are relatively enriched in the brain (Hawthorne and Pickard,
One key protein linking phosphoinositol metabolism with several dementias is synaptojanin 1 (SYNJ1). This phosphoinositide phosphatase hydrolyzes PI(4,5)P2, with SYNJ1 knock-out mice showed increased PI(4,5)P2 in neurons alongside defects in synaptic vesicle recycling (Cremona et al.,
Another subset of phosphoinositide conversion enzymes with key links to dementia is the phosphoinositide-3-kinases (PI3K). PI3K promotes downstream signaling
Together, these studies demonstrate how disruptions in phosphoinositide metabolism can be crucial to the development of neurodegenerative phenotypes. The following sections will go into more detail about phosphoinositide dyshomeostasis in specific neurodegenerative conditions.
The role of PIP species in different neuroinflammatory conditions.
Disease | PIP Species | Suspected roles in pathology | References |
---|---|---|---|
Alzheimer’s disease | PI(4)P | Key role in uptake systems including phagocytosis. | Stokes and Hawthorne ( |
PI(3,4)P2 | Mutations in the PI(3,4)P2 synthesis enzyme INPP5D increase genetic AD risk. Excess PI3K (generates PI(3,4)P2) activity in AD. | Lambert et al. ( |
|
PI(4,5)P2 | A genetic variant in PLCγ2, which breaks down PI(4,5)P2, protects against AD2, acts as a risk factor for AD. | McIntire et al. ( |
|
PI(3,4,5)P3 | Excess PI3K (generates PI(3,4,5)P3) activity in AD. | Heras-Sandoval et al. ( |
|
Parkinson’S disease | PI(4,5)P2 | Reduced PLC activity and PI(4,5)P2 metabolism in PD cortex, perhaps following the accumulation of α-synuclein which appears to inhibit PLC enzymes. Increased PI(4,5)P2 in PD patient substantia nigra. | Sekar and Taghibiglou ( |
PI(3,4,5)P3 | Excess PI3K (generates PI(3,4,5)P3) reduced activity in PD3) increased in PD. | Bernier et al. ( |
|
Huntington’S disease | PI(3)P | Inhibiting PIP-4 kinase (phosphorylates PI(3)P) reduces mHTT and rescues neurodegeneration in HD drosophila. | Al-Ramahi et al. ( |
PI(5)P | Inhibiting PIP-4 kinase (phosphorylates PI(5)P) reduces mHTT and rescues neurodegeneration in HD drosophila. | Al-Ramahi et al. ( |
|
Amyotrophic lateral sclerosis | PI(4)P | ALS risk gene VAPB is proposed to affect neurite extension during differentiation |
Genevini et al. ( |
PI(3,5)P2 | Non-synonymous variants in the PI(3,5)P2 phosphatase FIG4 found in 1–2% of ALS patients. LOF leads to reduced levels of PI(3,5)P2 and is suspected to affect autophagy. | Chow et al. ( |
Quite a large body of research outlines phosphoinositide dyshomeostasis in AD. The first study to highlight this was published in 1987 by Stokes and Hawthorne. They revealed reduced PIP4 and PI(4,5)P2 within the AD cortex when compared with controls (Stokes and Hawthorne,
Alterations in membrane phospholipid composition within AD following PIP dysregulation could result in changes to membrane structure and fluidity, which in turn is likely to influence the development of various characteristic AD pathologies (Zhu et al.,
Finally, many known AD risk genes (e.g., Phospholipase C Gamma 2 (PLCG2), inositol polyphosphate 5-phosphatase D (INPP5D), Phospholipase D3 (PLD3), CD2-associated protein (CD2AP), Phosphatidylinositol Binding Clathrin Assembly Protein (PICALM), Sodium/potassium/calcium exchanger 4 (SLC24A4)) are involved in phospholipid metabolism (Tan et al.,
Several studies have highlighted the specific roles of phosphoinositide dyshomeostasis in PD pathology. In one of these studies, PD and control membranes were prepared from the post-mortem prefrontal cortex and incubated with PI(4,5)P2 before the addition of dopamine to activate PLC. These membranes demonstrated reduced PLC activity, characterized by decreased PI(4,5)P2 metabolism, within the PD samples (Wallace and Claro,
In addition to altered PLC signaling, levels of phosphatase and tensin homolog (PTEN), another phosphoinositide phosphatase, are also altered in PD. Interestingly, in this same study, PI(3,4,5)P3 was found to be decreased, and PI(4,5)P2 increased, in substantia nigra samples from PD patient brains compared to age-matched controls (Sekar and Taghibiglou,
Phosphoinositide dyshomeostasis has also been observed in HD. For one, HTT and mHTT can be seen to interact with a variety of PIPs at membranes (Kegel et al.,
Studies by Al-Ramahi et al. (
Several studies have highlighted a potential role for phosphoinositol dyshomeostasis in the pathogenesis of ALS. Firstly, non-synonymous variants in the PIP phosphatase Factor-Induced Gene 4 (FIG4) appear in 1–2% of all ALS patients (Chow et al.,
Phosphoinositides have key roles in the brain, and therefore it should come as no surprise that both their levels and distribution are affected by a wide variety of neurodegenerative diseases. In several cases, this dyshomeostasis has been directly linked to disease pathology, thereby highlighting the potential of phosphoinositide-based therapies when looking to treat these devastating and often incurable conditions.
Having discussed both the function of microglia and PIPs in neurodegenerative disorders, the next section will explore the potential outcomes of PIP dyshomeostasis on specific microglial functions. The functions covered are TLR signaling, purinergic signaling, endocytosis, chemotaxis, and migration.
Toll-like receptors (TLRs) recognize conserved pathogen-associated molecular patterns (PAMPs) of bacteria, viruses, yeast, fungi, and parasites (Takeuchi et al.,
Upon activation, TLRs dimerize and recruit toll/interleukin 1 (TIR)-domain-containing adaptor proteins. These adaptor proteins are myeloid differentiation primary response protein 88 (MyD88, TLRs 1–2 and 4–9), TIR-domain containing adaptor protein (TIRAP, TLR 2 and 4), TIR domain-containing adaptor-interferon β (TRIF, TLR3 and 4), and TRIF-related adapter molecule (TRAM, TLR4; Takeda et al.,
Phosphoinositides, in particular PI(4,5)P2, have been shown to act as key regulators of TLR4 signaling (Le et al.,
In addition to modulating adaptor protein localization, PI(4,5)P2 can also have indirect effects on TLR signaling. Activated TLR4 is subsequently internalized
Furthermore, TLR9 can be seen to induce autophagosome/lysosomal fusion—a key event in autophagy—
Aging, a key risk factor for numerous neurodegenerative diseases (Hou et al.,
When closely examining links between TLRs and neurodegenerative disease, it quickly becomes apparent that the relationship between signaling and pathology is often complex. Increasing or decreasing the expression of various TLRs can have both protective and detrimental outcomes in a wide variety of neurodegenerative conditions (Rietdijk et al.,
The importance of TLR signaling in preventing the development of AD is highlighted by studies demonstrating how activation of TLR 2, 4, and 9 signaling can reduce brain pathology and plaque build-up (Tahara et al.,
Numerous studies demonstrate upregulated TLR signaling within PD. TLR upregulation within the PD brain is suspected to be responsible for the observed α-synuclein-induced microglial activation (Kouli et al.,
Having summarized the well-characterized roles of TLRs and phosphoinositols in neurodegenerative conditions, the next question is whether we can exploit this knowledge when considering potential therapeutics. As TLRs have been implicated in the pathology of numerous diseases, both neurodegenerative and otherwise, many studies have characterized the effects of both natural and synthetic TLR agonists and antagonists (Gambuzza et al.,
TLR4 activation to increase engulfment of misfolded protein could act as a promising treatment strategy within the early-AD brain. Potential candidates to activate TLR4 include the non-toxic LPS derivative monophosphoryl lipid A (Yousefi et al.,
As TLR signaling, particularly TLR4 signaling, is highly influenced by changing PI(4,5)P2levels, it may be possible to boost any protective effects by combining TLR-targeting and PI(4,5)P2 manipulating compounds. This could involve co-treating with drugs to increase PI(4,5)P2 levels when activating TLR4 and reducing PI(4,5)P2 when inhibiting TLR4. There are several options available for manipulating PI(4,5)P2 levels (Idevall-Hagren and De Camilli,
To conclude this section, TLR signaling, a key function of microglia, is dysregulated in numerous neurodegenerative conditions. This potentially allows for the possibility of using the same drug to treat multiple disorders. TLR signaling has strong links to phosphoinositide metabolism, another function known to be disrupted in the same conditions. These links could be exploited when investigating potential therapeutics.
The purinergic signaling system has wide-ranging implications for CNS function. This system consists of enzymes, transporters, receptors, and other proteins which facilitate the recognition, secretion, and degradation of extracellular nucleotides and nucleosides. Within the CNS, nucleotides [such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), and uridine diphosphate (UDP)] are released from cells in exosomes. ATP is often released from damaged cells following CNS injury (Neary et al.,
Microglia express the P1 receptors A1, A2A and A3 (Haskó et al.,
The above information demonstrates the crucial role of purinergic signaling regarding a wide variety of microglial functions.
All known P2X channels (except P2X5) have been demonstrated to be regulated by phosphoinositide signaling, with PIPs proving crucial cofactors for channel activity (Bernier et al.,
PI(4,5)P2 and PI(3,4,5)P3 have been demonstrated to increase P2X4 channel activity. Activity, including P2X4-mediated Ca2+ entry, can be stopped by depleting either PI(4,5)P2 or PI(3,4,5)P3 and rescued by intracellular injection of these lipids (Bernier et al.,
Pharmacological inhibition of PI(4,5)P2 synthesis has been demonstrated to reduce P2X7R current density (Zhao et al.,
Increasing evidence suggests the PI(4,5)P2 degradative enzyme PLCγ2 as an indirect regulator of numerous P2X channels
In addition to interaction with P2X channels, ATP and PI(4,5)P2 binding has been demonstrated to co-regulate key intracellular signaling proteins. This includes focal adhesion kinase, which has been demonstrated to impact microglial mobility (Choi et al.,
The above evidence demonstrates a clear regulatory function of phosphoinositide species, particularly PI(4,5)P2, with regards to purinergic signaling. This means that PIP dyshomeostasis within neurodegenerative disease will likely have substantial implications regarding microglial purinergic signaling and downstream phenotypes.
Purinergic signaling has well-established roles within numerous neurodegenerative disorders including AD, PD, HD, and ALS (Puchałowicz et al.,
P1 receptors are seen to be upregulated early in disease progression within the most affected areas of PD patient brains (Villar-Menéndez et al.,
P2X receptors are also acknowledged to play important roles in neurodegenerative disease development. P2X7R is the most widely studied regarding its roles in neurodegeneration, following observations that it is upregulated in microglia from a variety of conditions including AD and PD (McLarnon et al.,
P2Y receptors are also dysregulated in a variety of neurodegenerative conditions. Within AD microglia, P2Y signaling can be seen to affect microglial migration, chemokine and cytokine production, endocytosis, phagocytosis, Aβ metabolism, and oxidative stress responses (Erb et al.,
Whist more work needs to be done to thoroughly characterize the roles of microglial purinergic signaling in neurodegenerative disease, these signaling pathways have clear implications regarding dementia pathology.
Drugs targeting purinergic signaling are showing great promise regarding the treatment of a variety of neurodegenerative disorders.
Several A2A receptor antagonists have been characterized and investigated in clinical trials on PD patients, showing various degrees of success. So far, however, despite the benefits of A2A antagonism seen
P2X7 antagonists appear to reduce pathologies in several neurodegenerative disorders, including AD and PD (Burnstock and Knight,
Given the potential of P2XR7 and P2XR4 inhibition as potential therapeutic targets for neurodegenerative disorders, and that these channels are activated by PIPs, it may be the case that dual P2X and PIP synthesis inhibition could act as a potential therapeutic. As mentioned in the previous section on TLR signaling, there are several options available for modulating PIP levels (Idevall-Hagren and De Camilli,
In summary, purinergic signaling, a key regulator of microglial function, is dysregulated in numerous neurodegenerative disorders. This process has strong links to phosphoinositide metabolism. These links could be exploited when investigating potential therapeutics.
Microglia, like all tissue-resident macrophages, are dedicated phagocytes tasked with immune surveillance and the elimination of pathogens. These cells can recognize, engulf and destroy foreign bodies. In addition to their immuno-protective role, microglia also perform important housekeeping tasks such as removing apoptotic cells and mediating synaptic pruning during development (Wake et al.,
During phagocytosis and macropinocytosis, large vacuoles are known as phagosomes, and macropinosomes form
Clathrin-mediated endocytosis is the major entry route for extracellular hormones and signaling factors and serves to regulate the internalization of transmembrane receptors as well as the recycling of pre-and postsynaptic membrane proteins (Le Roy and Wrana,
The following sections discuss the role of PIPs in the above described endocytic processes and speculated involvement of these lipids is summarized in
Suspected involvement of PIP species in various forms of endocytosis.
Type of endocytosis | PIP species involved | Mechanism | References |
---|---|---|---|
Phagocytosis | PI(4,5)P2 | Increase following target recognition allows the formation of pseudopodia. Later reduction essential for the completion of phagocytosis. | Coppolino et al. ( |
PI(3)P | The transient increase allows maturation and sealing of phagosomes. | Vieira et al. ( |
|
Macropinocytosis | PI(4,5)P2 | Enriching this PIP in membrane ruffles stimulates macropinocytosis. | Donaldson ( |
PI(3)P | Participates in vacuole formation. | Yoshida et al. ( |
|
Clathrin-mediated endocytosis | PI(4,5)P2 | Required for the invagination of clathrin-coated vesicles. | Antonescu et al. ( |
Caveolae-mediated endocytosis | PI(4,5)P2 | Accumulates at the rim of caveolae vesicles. | Nunes and Demaurex ( |
When microglia initially encounter phagocytic targets, extracellular signals must be conveyed across the plasma membrane to initiate the complex cellular behaviors that culminate in uptake. It is becoming increasingly apparent that PIPs play a prominent role in relaying this information. Indeed, both the detection of ligands by transmembrane phagocytic receptors and the ruffling of membranes during macropinocytosis are accompanied by local changes in PIP composition (Gillooly et al.,
PI(4,5)P2 and its metabolites (
Roles of PI(4,5)P2 in early phagocytosis.
PI(4,5)P2 promotes the activation of several actin-regulatory proteins which encourage filament assembly and inhibit disassembly (Saarikangas et al.,
In addition to the consequences that PI(4,5)P2 metabolism has on cytoskeletal dynamics, the breakdown of this PIP to its secondary metabolites also has important ramifications in the phagocytic process. PLCγ-mediated hydrolysis of PI(4,5)P2 leads to the formation of DAG and Ins(1, 4, 5)P3 (IP3). DAG generation coincides in space and time with the disappearance of PI(4,5)P2. Interestingly, though neither DAG nor IP3 is essential for particle engulfment, inhibition of PLCγ blocks the phagocytic response (Botelho et al.,
Like other 3-polyphosphoinositides, PI(3,4,5)P3 levels are scarce in unstimulated cells. However, PI(3,4,5)P3 is quickly generated following activation of immune receptors. The metabolism of PI(3,4,5)P3 is strictly and dynamically regulated, and in general restricted to the cytosolic side of the cell membrane (Palmieri et al.,
Though its cellular concentration is comparatively low, the PIP PI(3)P is also critically involved in the maturation of phagosomes. In mammalian cells, PI(3)P is found mainly at the cytoplasmic leaflet of early endosomes and in intraluminal vesicles of multivesicular bodies (Kaminska et al.,
A central role for PIPs as spatial landmarks for membrane trafficking in other forms of endocytosis has emerged (Cremona and De Camilli,
Several studies have documented the presence of PI(3,4)P2 in macropinosomes. This PIP appears to be generated by SHIP2 and broken down by INPP4B (Hasegawa et al.,
Whilst the core components of caveolae are not known to associate with PIPs directly, the dynamin-related ATPase EHD2 binds PI(4,5)P2-rich membranes before recruitment to caveolae containing vesicles (He et al.,
One of the principal roles of microglia in neurodegeneration is the clearance of protein aggregates, myelin debris, and apoptotic cells in an attempt to maintain healthy brain homeostasis. Many neurodegenerative conditions present with increasing accumulation of toxic extracellular proteins such as Aβ plaques in AD, and increased apoptosis of cells such as the loss of dopaminergic neurons in PD. It is therefore clear that alterations in microglial phago and endocytosis would have important implications regarding the progression of neurodegenerative conditions.
FcR-mediated phagocytosis and complement activation play a critical role in the removal of plaques from the AD brain (Lee and Landreth,
In addition to observations in AD,
As discussed in the previous section, microglial phagocytosis plays an important role in the neuroimmune response to neurodegenerative conditions. As such it presents a tempting target for therapeutic intervention. However, it is worth remembering one of the clinical symptoms of AD is the chronic loss of synapses caused by microglial phagocytic engulfment (McQuade and Blurton-Jones,
Cell migration is crucial to the function of microglia, allowing them to patrol their region of interest and respond to sites of damage. Microglia react rapidly to damage signals with a positive chemotactic response. Upon detection of these signals, microglia undergo complex molecular and cytoskeletal changes that polarize the cell towards the direction of the damage site. Once stimulated to migrate, cells form a coordinated outgrowth of protrusions and adhesions, which results in translocation of the cell body by contraction towards the adhering zones. Finally, the adhesions are disassembled and the rear of the cell is retracted (Smolders et al.,
Microglia mobility can be broadly divided into two main functional modes; surveillance and chemotaxis. Both these systems involve altering the cytoskeletal structure of the microglia using the high amounts of filamentous actin in motile bundles present in microglial cells (Capani et al.,
Microglia detect damage (
Functional role of phosphoinositides in cell migration. The binding of a chemoattractant to G-protein coupled receptors (e.g., P2Y12R) in the cell membrane releases the Gα heterodimer from the heterotrimeric Gα proteins. Dissociated Gα proteins stimulate PI(3,4,5)P3 production from PI(4,5)P2
P2Y12R has also been reported to be linked to a potassium channel, and ATP/ADP-induced activation of P2Y12R elicits an outward potassium current in microglia (Swiatkowski et al.,
Interaction with PIP species is crucial regarding actin assembly, with these lipids facilitating the crosslinking and linking of actin to the plasma membrane by binding with several different actin-binding proteins (ABPs;
Cofilin proteins are a family of ABPs which are structurally and functionally related to gelsolin. These proteins bind to both G and F-actin and cause depolymerization at the minus end of filaments, thereby preventing their reassembly. Both PI(4,5)P2 and PI(3,4,5)P3 bind to cofilin and inhibit its activity (Ojala et al.,
α-Actinin belongs to the spectrin gene superfamily. This protein connects actin filaments to integrins and serves as a scaffold to integrate signaling components at adhesion sites and promote bundling of actin filaments (Otey and Carpen,
The Ezrin/radixin/moesin (ERM) protein family provides a regulated linkage between the plasma membrane and the underlying actin cytoskeleton (Tsukita and Yonemura,
Septins are a group of highly conserved GTP-binding proteins that assemble into filaments and are increasingly recognized as a crucial component of the cytoskeleton (Mostowy and Cossart,
Myosin I is a monomeric, actin-based motor protein with ATPase activity that has been shown to function in the membrane–cytoskeletal interactions, including vesicle transport along actin filaments and regulation of plasma membrane tension. Myosin I molecules have a tail homology (TH) domain that contains a putative phospholipid-binding PH domain. Previous studies have shown that the TH domain preferentially binds to acidic phospholipids such as phosphatidylserine and PI(3,4,5)P2. These phospholipids are relatively abundant in biological membranes and their concentrations do not appear to change a great deal in response to intracellular signaling. In contrast, PI(3,4,5)P3 levels are highly regulated and function as signaling mechanisms for myosin (Chen et al.,
Many neurodegenerative conditions present with alterations in microglial migration and distribution. Microglia follow gradients of chemokines towards damaged and dying cells, which by definition are present in these disorders.
The net migration of microglia induced by deposits of Aβ in AD is well documented. This process acts to concentrate microglia around Aβ deposits in an attempt to neutralize or prevent further damage. Increased levels of a wide range of chemokines have been reported in AD patients (Koenigsknecht-Talboo and Landreth,
Targeting chemotaxis to treat neurodegeneration represents a very nuanced problem. While microglia do have a protective role in many forms of neurodegenerative disease, they also have a detrimental role. While an increased number of microglia may be able to reduce damage and clear extracellular proteins they can also initiate a large, potentially damaging neuroinflammatory response. As such promoting chemotaxis to encourage microglia response to damage may be counterproductive while at the same time reducing the neuroimmune response is also unadvised. A few therapies linked to chemotaxis have been investigated, however. TREM2 is a receptor upstream of PLCγ2 in microglia. Sequence variations in TREM2 have been demonstrated to increase the risk of AD (Sims et al.,
The microglial function is severely impaired in a variety of ways within neurodegenerative conditions, with these cells typically showing heightened activation states from early stages of disease development, often before symptom onset. Alongside disturbances in microglial homeostasis, disruptions in phosphoinositide levels and metabolism are also seen in many of these same conditions. These PIPs appear to play important roles in the regulation of numerous key microglial functions. Together, these observations suggest that the observed microglial dysfunction may arise in part as a result of this lipid dyshomeostasis.
Further research into both the role of microglia and PIP dyshomeostasis within neurodegenerative disease could provide us with much-needed therapeutics for treating these presently incurable conditions. It may be that co-manipulating microglial functions alongside PIP levels could allow us to boost the effectiveness of targeted therapeutics, thus bringing us closer to the ultimate goal of a world without dementia.
TP and EM contributed equally to the researching and drafting of the work presented here. All authors contributed to the article and approved the submitted version.
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.