Your new experience awaits. Try the new design now and help us make it even better

REVIEW article

Front. Mol. Biosci., 26 June 2025

Sec. Molecular Diagnostics and Therapeutics

Volume 12 - 2025 | https://doi.org/10.3389/fmolb.2025.1622186

This article is part of the Research TopicEstrogens and Neurodegeneration: a Link Between Menopause and Alzheimer’s Diseases in WomenView all 5 articles

Hormonal modulation, mitochondria and Alzheimer’s prevention: the role of GLP-1 agonists and estrogens

Fernando Lizcano,,,
Fernando Lizcano1,2,3,4*Daniela Sanabria,Daniela Sanabria3,4Eliana Aviles,Eliana Aviles3,4
  • 1Center of Biomedical Investigation (CIBUS), Universidad de La Sabana, Chía, Colombia
  • 2School of Medicine, Universidad de La Sabana, Chía, Colombia
  • 3Fundación Cardioinfantil-Instituto de Cardiología, Bogotá, Colombia
  • 4School of Medicine, Universidad del Rosario, Bogotá, Colombia

Alzheimer’s disease (AD) is the most prevalent cause of dementia worldwide, disproportionately affecting women and lacking effective disease-modifying therapies. While traditional approaches have focused on amyloid β (Aβ) plaques and tau pathology, emerging evidence highlights the role of metabolic dysfunction, mitochondrial impairment, and hormonal signaling in the pathogenesis of AD. Estrogens exert neuroprotective effects by modulating synaptic plasticity, enhancing mitochondrial bioenergetics, and reducing oxidative stress and inflammation. Similarly, glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for the treatment of type 2 diabetes, have demonstrated promising cognitive benefits, potentially mediated through improved insulin signaling, neuronal survival, and reduced β-amyloid (Aβ) and tau burden. This review explores the converging mechanisms through which estrogens and GLP-1RAs may act synergistically to prevent or delay the onset of AD. We examine the influence of sex differences in mitochondrial dynamics, estrogen receptor distribution, and GLP-1 signaling pathways, particularly within central nervous system regions implicated in AD. Preclinical studies using GLP-1-estrogen conjugates have shown enhanced metabolic and neuroprotective outcomes, accompanied by reduced systemic hormonal exposure, suggesting a viable therapeutic strategy. As the global prevalence of AD continues to rise, especially among postmenopausal women, dual agonism targeting estrogen and GLP-1 receptors may represent a novel, physiologically informed approach to prevention and intervention. Ongoing clinical trials and future research must consider sex-specific factors, receptor polymorphisms, and brain-region selectivity to optimize the translational potential of this combined strategy.

1 Introduction

Alzheimer’s disease (AD) represents the most prevalent form of dementia to date. According to the World Health Organization (WHO), over 55 million people worldwide live with some form of dementia, with approximately 10 million new cases reported each year. The prevalence of this condition varies by gender, with an estimated 8.1% of women and 5.4% of men over the age of 65 experiencing some form of dementia, nearly 70% of which corresponds to Alzheimer’s disease (AD) (Livingston et al., 2020; Montero-Odasso et al., 2020; OMS, 2021).

The etiology of AD is complex and multifactorial, characterized by progressive neuronal aging, synaptic loss, and dysfunction of neural networks (Knopman et al., 2021). Pathologically, AD is marked by the extracellular accumulation of β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau (τ) protein (Shi et al., 2020). Aβ plaques originate from the aberrant processing of amyloid precursor protein (APP), mediated sequentially by β- and γ-secretases. This cleavage generates the membrane-bound C-terminal fragment CTF99, which is subsequently processed by γ-secretase to release Aβ peptides of 40–42 amino acids (Neha and Parvez, 2023). The aggregation of these peptides into oligomers and their subsequent deposition as extracellular senile plaques is facilitated by interactions with apolipoproteins and proteoglycans, contributing to the synaptic dysfunction and neurodegeneration that define the disease (Arjmand et al., 2024).

Additionally, the hyperphosphorylation of tau protein disrupts its binding to neuronal microtubules. Hyperphosphorylated tau induces the formation of insoluble protein aggregates and, ultimately, intracellular tangles. This abnormal accumulation interferes with axonal transport and promotes axonal degeneration (Kinney et al., 2018).

Therapeutic efforts aimed at neutralizing these pathological processes have thus far yielded limited results. Monoclonal antibodies targeting Aβ, such as aducanumab, lecanemab, and donanemab, have not demonstrated clinically meaningful efficacy (Terao and Kodama, 2024). Antibodies directed against tau protein, including semorinemab, tilavonemab, and gosuranemab, have shown unpromising preliminary results and fail to improve global patient functionality (Florian et al., 2023; Monteiro et al., 2023). In general, these treatments only modestly reduce disease progression, and their clinical application remains limited due to a lack of effectiveness (Livingston et al., 2020; Walsh et al., 2021; van Dyck et al., 2023).

For these reasons, recent investigations have expanded the focus to additional disease mechanisms. Notably, alterations in cholinergic signaling, neuroinflammation involving microglial activation, and calcium dysregulation have emerged as relevant contributors to AD pathogenesis. Moreover, increasing attention has been given to metabolic dysfunction, particularly in glucose metabolism and the bioenergetic role of estrogens, as potentially essential triggers of AD. Recent research has highlighted the therapeutic potential of glucagon-like peptide-1 receptor agonists (GLP-1RAs) beyond glucose metabolism, particularly in neurodegenerative diseases such as Alzheimer’s disease (AD). These agents have demonstrated neuroprotective effects, including the reduction of oxidative stress, enhancement of mitochondrial function, and attenuation of neuroinflammation. Furthermore, emerging evidence suggests that GLP-1RAs may modulate central insulin signaling and synaptic plasticity, pathways that are increasingly implicated in the pathophysiology of AD. In this context, exploring the mechanistic relationship between GLP-1 receptor activation and mitochondrial function in the brain may provide valuable insights into novel therapeutic strategies for AD (Liang et al., 2024).

This review highlights estrogens’ role in the central nervous system, with emphasis on their regulatory functions in mitochondrial metabolism. It also explores their potential as a pharmacological target for AD prevention.

2 Neuronal metabolism and Alzheimer’s disease

Neurons are subject to systemic metabolic regulatory processes involving carbohydrates and lipids. Metabolic disturbances that elevate cardiovascular risk also affect the cerebral microvasculature, contributing to cognitive decline and the development of dementia, including AD. Impaired cerebral perfusion compromises white matter integrity, deteriorates neural connectivity, and facilitates neurodegenerative processes (Kellar and Craft, 2020; Hernandez-Rodriguez et al., 2022).

The metabolic events most closely associated with AD include insulin resistance, hyperglycemia, lipid dysregulation, mitochondrial dysfunction, and oxidative stress. All these factors promote disease progression. While the exact mechanisms remain incompletely understood, type 2 diabetes mellitus (T2DM) is strongly linked to the pathogenesis of AD (Mittal and Katare, 2016). Both conditions share overlapping pathological mechanisms that impair cognitive function, eventually leading to Aβ deposition in the brain. Furthermore, chronic inflammation, oxidative stress, dyslipidemia, mitochondrial dysfunction, impaired insulin signaling, and synaptic dysfunction are all common features of T2DM and AD (Kapogiannis et al., 2019; Bernabe-Ortiz and Carrillo-Larco, 2022).

At the molecular level, central or peripheral insulin resistance can result from reduced insulin receptor expression, decreased binding affinity, and disruption of downstream signaling pathways (Tatar et al., 2003). Insulin exerts its cellular effects through two primary pathways: the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, the latter of which plays a crucial role in cell growth and survival. Insulin receptor activation triggers the recruitment of insulin receptor substrate (IRS) proteins, which, when phosphorylated on tyrosine residues, activate PI3K-Akt signaling. In contrast, serine phosphorylation of IRS proteins inhibits this signaling cascade (Craft and Watson, 2004).

The ratio of serine-phosphorylated IRS to total IRS is widely used as a biomarker of insulin resistance in both brain and peripheral tissues. An elevated ratio reflects greater insulin resistance. Studies have demonstrated cerebral insulin resistance in AD patients using ex vivo insulin stimulation and measurement of this ratio in brain tissue (Bassil et al., 2014).

Consequently, impaired insulin sensitivity reduces PI3K-Akt activation and downstream phosphorylation of proteins essential for neuronal survival, such as glycogen synthase kinase-3β (GSK3β). This promotes tau hyperphosphorylation and neurofibrillary tangle formation, hallmark features of AD. Additionally, defective insulin signaling contributes to neuronal energy deficits by decreasing glucose uptake and reducing the expression and function of glucose transporters GLUT3 and GLUT4 in the central nervous system (Schulingkamp et al., 2000).

Moreover, reduced cerebral vascularization observed in T2DM leads to chronic hypoxia, which is implicated in the progression of AD. Decreased oxygen supply disrupts neuronal energy homeostasis, induces oxidative stress, and compromises mitochondrial function (Neth and Craft, 2017). Under hypoxic conditions, cells activate adaptive responses mediated by hypoxia-inducible factor-1 (HIF-1), which regulates genes involved in angiogenesis, cell survival, and glucose metabolism. However, sustained HIF-1 activation in the context of neurodegeneration may exacerbate inflammation and promote Aβ production, thereby worsening synaptic dysfunction and neuronal damage (Zhang et al., 2007).

In addition to impaired glucose metabolism, extensive clinical, preclinical, and epidemiological data have linked lipid metabolic dysfunction to AD risk. Lipids are essential for numerous brain processes, including synaptic regulation, myelin sheath formation, and energy storage. Given the brain’s high lipid content, numerous studies have identified early alterations in specific lipid classes in AD, such as decreased plasmalogens, sulfatides, and elevated ceramides (Han, 2005). Lipids also modulate APP trafficking and processing, influencing neurotoxic Aβ peptide formation (Penke et al., 2018).

Apolipoprotein E (APOE) is a key lipid-transporting protein primarily involved in cholesterol and phospholipid metabolism in both peripheral tissues and the central nervous system. It exists in three major isoforms in humans -APOE2, APOE3, and APOE4- which differ by single amino acid substitutions and exhibit distinct structural and functional properties. While APOE3 is the most prevalent and considered the “neutral” isoform, APOE2 is often associated with protective effects against neurodegeneration. In contrast, APOE4 has been consistently linked to increased risk and earlier onset of Alzheimer’s disease (AD), possibly due to its detrimental influence on lipid homeostasis, mitochondrial integrity, and neuroinflammatory pathways (Volgman et al., 2024; Guo et al., 2025).

Apolipoprotein E4 (ApoE4) is a major genetic risk factor that connects lipid metabolism disorders with AD. Recent studies have highlighted lipid droplet accumulation in ApoE4 carriers, especially within phagocytic cells. In these microglia, lipid overload impairs phagocytosis and increases inflammatory responses, contributing to neurodegeneration. Lipid dyshomeostasis interacts with several AD pathogenic pathways, including amyloidogenesis, mitochondrial dysfunction, oxidative stress, neuroinflammation, and myelin degeneration (Yin, 2023; Jackson et al., 2024).

The human APOE gene encodes the 34-kDa lipid-binding protein ApoE, which mediates lipid transport throughout peripheral organs and between brain cells (Hauser et al., 2011). Compared to the common ε3 isoform, the ε4 variant is the strongest genetic risk factor for late-onset AD (Houlden et al., 1998), while the ε2 isoform significantly reduces risk (Reiman et al., 2020). Each ApoE4 allele increases AD risk three- to fourfold and lowers the age of onset by approximately 8 years (Neu et al., 2017).

ApoE4 also exerts pathological effects by disrupting lipid concentration homeostasis. ApoE4 carriers exhibit higher plasma levels of total cholesterol and triglycerides, but reduced HDL cholesterol, while ApoE2 carriers show the opposite pattern (Notkola et al., 1998; Huang and Mahley, 2014). Additionally, ApoE4 enhances cytosolic phospholipase A2 (cPLA2) activity, increasing arachidonic acid production. ApoE4-associated pathology can be mitigated by DHA-rich (docosahexaenoic acid) diets but worsens with high-cholesterol intake (Wang et al., 2005; Grimm et al., 2017).

Cholesterol, sphingolipids, and polyunsaturated fatty acids are particularly implicated in AD pathogenesis. Understanding lipid alterations may lead to therapeutic strategies targeting lipids, which could vary depending on disease stage, ApoE status, and metabolic profiles [28]. Other genes related to lipid metabolism and AD risk include TREM2, APOJ, PICALM, ABCA1, and ABCA7, all involved in lipid transport. Additionally, SREBP-2, a key regulator of cholesterol metabolism, has also been genetically associated with increased AD risk (Zhao et al., 2015; Kober and Brett, 2017; Shimano and Sato, 2017; Yin, 2023).

3 The mitochondrial theory of Alzheimer’s disease

Mitochondria possess their own genome, which enables the synthesis of proteins essential for their function. This genome encodes 13 subunits of the complexes that constitute the electron transport chain (ETC), while the remaining subunits, along with other mitochondrial proteins, are encoded by nuclear DNA. Due to the absence of histones, mitochondrial DNA (mtDNA) is particularly vulnerable to oxidative stress. Moreover, its limited capacity for repair and recombination increases the accumulation of mutations that compromise mitochondrial function (Elson et al., 2006). Structural alterations in mtDNA are exacerbated in patients with AD, with microscopic analyses revealing abnormally small mitochondria and disrupted cristae, particularly in the mammillary bodies and certain hypothalamic regions (Baloyannis et al., 2015; Baloyannis et al., 2016). Several studies have also reported a higher incidence of oxidized nucleotides and an increased number of mutations in the coding regions of mtDNA in AD patients (Wang et al., 2005).

Although little is known about the epigenetic regulation of mtDNA, significant differences in mtDNA methylation have been observed between individuals with AD and healthy controls (Stoccoro et al., 2017). Mitochondrial function depends on a dynamic equilibrium between fusion and fission. Mitochondrial fusion allows the merging of individual organelles, promoting the exchange of materials and dilution of damaged components, thus maintaining mitochondrial efficiency. In contrast, fission generates smaller mitochondria, facilitating the selective removal of dysfunctional organelles through mitophagy and ensuring proper mitochondrial distribution according to cellular energy demands.

In AD, increased mitochondrial fission leads to excessive fragmentation. Postmortem studies have shown elevated expression of mitochondrial fission proteins in the prefrontal cortex of AD patients (Manczak et al., 2011). Several experimental studies have demonstrated that mitochondrial dysfunction is an early and central feature in the pathogenesis AD. In rodent models, intracerebroventricular (icv) administration of streptozotocin (STZ) has been widely used to mimic sporadic AD by inducing brain insulin resistance, oxidative stress, and cognitive decline, without affecting peripheral glycemic control. Unlike systemic administration, which causes selective pancreatic β-cell destruction via GLUT2 transporters and is used to model type 1 diabetes mellitus (T1DM), icv-STZ acts directly on neurons in the central nervous system (CNS). Notably, STZ-treated animals exhibit alterations in mitochondrial dynamics, including increased expression of fission proteins such as Drp1 and Fis1, accompanied by decreased levels of fusion-related proteins like Mfn2 and OPA1, particularly in the hippocampus and in the prefrontal cortex (Paidi et al., 2015; Joshi et al., 2018). Transgenic AD models such as APP/PS1 mice, which overexpress mutant human amyloid precursor protein and presenilin-1, have also revealed mitochondrial fragmentation and respiratory deficits, reinforcing the hypothesis that impaired mitochondrial dynamics and mitophagy are mechanistically linked to AD pathology. These findings suggest that mitochondrial fragmentation and bioenergetic failure contribute to neurodegeneration and cognitive impairment in this model.

Given that mitochondrial bioenergetic alterations appear early in the disease course, they are considered potential primary events underlying synaptic failure, neuroinflammation, oxidative stress, and neuronal loss (Joshi et al., 2018). Mitochondria are central to ATP production via oxidative phosphorylation and regulate calcium homeostasis, cell growth, and metabolism (Du et al., 2010; Peggion et al., 2024).

One hallmark of AD is the impaired removal of damaged mitochondria due to defective autophagy. A particular alteration involves lysosomal dysfunction, which hinders the degradation of structurally damaged mitochondria, leading to cellular toxicity (McGill Percy et al., 2025). Furthermore, mitochondrial impairment can, in turn, disrupt endolysosomal processes, as endolysosomal biogenesis may be modulated in response to mitochondrial damage (Fernandez-Mosquera et al., 2017). Studies have shown that mitochondrial dysfunction alters lysosomal function and morphology, either through exposure to mitochondrial toxins or deletion of proteins such as apoptosis-inducing factor (AIF), PTEN-induced kinase 1 (PINK1), or the ubiquitin ligase Parkin (Demers-Lamarche et al., 2016).

In AD, dysfunctional mitochondria accumulate and exacerbate lysosomal degradation bottlenecks. Affected neurons exhibit mitochondrial membrane potential loss, resulting in microtubule network disintegration and impaired autophagic flux toward lysosomes (Silva et al., 2017; Brewer et al., 2020). Aβ-induced oxidative stress further disrupts mitochondrial mobility and function (Brewer et al., 2020), establishing a negative feedback loop wherein Aβ exacerbates mitochondrial dysfunction, which in turn promotes further Aβ accumulation.

Mitochondrial dysfunction also contributes to tau pathology by increasing τ oligomer levels and shifting the monomer–oligomer balance toward toxic oligomers (Weidling et al., 2020). During oxidative phosphorylation, mitochondria generate and scavenge reactive oxygen species (ROS). However, persistent ROS overproduction exceeding antioxidant capacity leads to damage of cellular macromolecules, including phospholipids, proteins, and nucleic acids, compromising cellular function (Lane C. A. et al., 2018).

Elevated ROS levels can also result from Aβ modifications; for instance, the Met35 residue of Aβ, along with upregulated oxidases such as NADPH oxidases and monoamine oxidase B (MAO-B), increase ROS production. Moreover, Aβ interactions with excess metals-such as Fe2+, Cu2+, and Zn2+-further elevate oxidative stress (Lane D. J. R. et al., 2018; Bai et al., 2022).

4 Role of estrogens in neuronal function

Estrogens are steroid hormones primarily produced in the ovaries of women of reproductive age. Their primary biological activity is mediated by receptors belonging to the nuclear receptor superfamily, which function as transcription factors that modulate gene expression. After crossing the plasma membrane-facilitated by their steroid structure-estrogens bind to cytoplasmic receptors, which translocate to the nucleus and interact with DNA to regulate transcription (Lonard and O'Malley, 2006).

Estrogen receptors exist in two main isoforms, ERα and ERβ, both widely distributed throughout the body (Matthews and Gustafsson, 2003). These receptors form dimers and bind to specific DNA sequences known as estrogen response elements (EREs) in the promoter regions of target genes. Notably, approximately one-third of estrogen-regulated genes lack canonical EREs, suggesting alternative regulatory mechanisms (Johri et al., 2024; Peralta and Lizcano, 2024). Molecular and biochemical studies have shown that estrogens may also exert transcriptional effects via protein–protein interactions with other transcription factors (Aranda and Pascual, 2001; Marino et al., 2006; Mauvais-Jarvis et al., 2013).

Many estrogenic effects are not genomic and occur more rapidly than expected from transcriptional activation. The discovery of the G-protein–coupled estrogen receptor (GPER1) in the early 2000s provided insight into these non-genomic mechanisms (Nilsson et al., 2011). GPER1 mediates rapid signaling cascades involving adenylate cyclase, cyclic AMP, protein kinase A, and other second messengers. GPER1 mRNA and protein have been detected in blood vessels and cardiac tissue across various species (Haas et al., 2009). Expression in adipocytes, hepatocytes, and myocytes is more variable, and the precise in vivo role of GPER1 remains under debate (Meyer et al., 2011; Hewitt et al., 2017; Luo and Liu, 2020).

Ligand-independent actions of estrogen receptors (ERs) have also been described, particularly in the uterus, where ERα can be activated by growth factor pathways (e.g., IGF-1), leading to receptor recruitment to chromatin in the absence of estrogen binding (Meyer et al., 2011; Hewitt et al., 2017) (see Figure 1).

Figure 1
www.frontiersin.org

Figure 1. Estrogen signaling mechanisms. (A) Genomic signaling: Estrogens cross the plasma membrane and bind to the cytoplasm’s estrogen receptors (ERs). The estrogen-ER complex moves into the nucleus, forming homodimer and/or heterodimer complexes. These complexes bind to specific estrogen-sensitive elements (EREs) in DNA or recruit transcription factors. (B) Non-genomic signaling: Estrogens can perform a non-genomic effect by binding to their receptors on the plasma membrane. Additionally, some ERb are in the plasma membrane that induce the signaling cascade. Non-genomic information is established by extracellular signaling that stimulates second messengers in the cytoplasm; Responses are mediated by specific G-protein-coupled (GPER) receptors or estrogen receptors on the membrane. Finally, non-genomic action can indirectly increase gene expression.

Estrogens play a multifaceted role in the central nervous system (CNS), influencing synaptic plasticity, neuronal development, and survival in newly formed spinal synapses, as well as promoting neural stem cell proliferation and maintaining the integrity of the blood-brain barrier (McCullough et al., 2003; Mukai et al., 2010; Frick et al., 2015; Na et al., 2015). Both neuron- and astrocyte-derived estrogens are believed to contribute significantly to neuroprotection and cognitive function through interactions with ERs expressed in multiple brain regions (McEwen and Woolley, 1994; McEwen et al., 1995; Azcoitia et al., 2001).

Preclinical and human studies have shown that ERα is abundantly expressed in the hypothalamus, particularly in the preoptic area (POA), ventromedial nuclei (VMN), amygdala, and periventricular nuclei (PV). ERβ exhibits a similar distribution, maintaining high expression in the POA, bed nucleus of the stria terminalis (BNST), PV, and supraoptic nuclei (Laflamme et al., 1998; Azcoitia et al., 2001; Kruijver et al., 2003; Mitra et al., 2003; Kelly and Ronnekleiv, 2012). ERβ is also expressed in the hippocampus, amygdala, and cerebral cortex, where it participates in adult neurogenesis, synaptic plasticity, and new neuron formation (Weiser et al., 2008).

Postnatal expression of ERβ tends to decline, but it remains present in microglia, oligodendrocytes, and specific brain regions, such as the hypothalamus and amygdala (Vargas et al., 2016). ERβ signaling has been associated with several potential therapeutic benefits in CNS disorders: (1) it enhances GABAergic over glutamatergic signaling, exerting anticonvulsant effects (Veliskova and Desantis, 2013); (2) promotes oligodendrocyte maturation and myelination (Vargas et al., 2016; Karim et al., 2018); (3) modulates microglial activation and reduces inflammation (Valdes-Sustaita et al., 2021); and (4) supports serotonergic neurons, providing antidepressant effects (Suzuki et al., 2006). In both rodent models and postmenopausal women, ERβ ligands have shown beneficial effects on anxiety, depression, epilepsy, and multiple sclerosis (Warner and Gustafsson, 2015; Jellinger, 2024). However, clinical outcomes in humans have been inconsistent, potentially due to alternative splicing variants of ERβ, which may alter therapeutic responsiveness (Kim et al., 2018; Ulhaq and Garcia, 2021). Some natural compounds with estrogenic effects, such as polyphenols, have a beneficial impact on neurons by mitigating oxidative stress, inflammation, and apoptosis. However, their direct effects on the progression of Alzheimer’s disease have not been established (Abdelsalam et al., 2023).

Estrogens can also be synthesized de novo in the brain by neurons and astrocytes, starting from cholesterol (Blakemore and Naftolin, 2016). Moreover, local steroid metabolism in the brain can produce estrogens via aromatase, the enzyme responsible for converting androgens into estrogens (Gillies and McArthur, 2010; Brann et al., 2022). Aromatase expression varies across brain regions, with high levels found in the cerebellum, amygdala, hippocampus, and white matter. While sex differences in expression are not apparent in these regions, elevated aromatase levels have been reported in the hypothalamus—specifically in the POA and VMN—of male animals, suggesting regulation by circulating testosterone, which is subsequently converted to estradiol (E2) (Gillies and McArthur, 2010).

5 Estrogen effects on mitochondrial function

It is also important to consider the impact of estrogens on mitochondrial function. Mitochondria play a critical role in regulating cell survival and apoptosis, and the respiratory chain is a principal structural and functional target of estrogenic activity. Estrogens exert protective effects against oxidative stress by promoting the translocation of specific cytosolic enzymes into mitochondria, thereby shielding mitochondrial DNA (mtDNA) from free radical-induced damage (Leclere et al., 2013; Arjmand et al., 2024).

The distribution of ERα and ERβ in patients with AD varies considerably across brain regions. In women with AD, increased ERα expression has been observed in certain hippocampal areas, whereas levels are lower in hypothalamic nuclei and the medial mammillary nucleus (Hestiantoro and Swaab, 2004). However, overall, ERα has not been consistently implicated in AD pathogenesis. In contrast, growing evidence supports a protective role for ERβ, which appears to influence both disease risk and progression. In animal models, ERβ overexpression has been associated with reduced Aβ plaque deposition. Human studies have reported decreased ERβ levels in the frontal cortex of women with AD (Long et al., 2012; Tian et al., 2013).

The presence of estrogen receptors within mitochondria was initially identified in MCF-7 breast cancer cell lines and later confirmed in brain cells. Estrogens may influence mitochondrial function through both direct and indirect mechanisms. Specifically, ERβ upregulates nuclear respiratory factor 1 (NRF-1), which in turn stimulates the expression of mitochondrial biogenesis regulators, including mitochondrial transcription factor A (TFAM), and multiple subunits of the mitochondrial respiratory chain (MRC). These factors contribute to the regulation of mitochondrial gene expression and the maintenance of mitochondrial homeostasis (see Figure 2).

Figure 2
www.frontiersin.org

Figure 2. Los estrógenos pueden inducir la expresión de genes que aumentan la función mitocondrial, como SIRT3, PGC-1α, NRF1. ERβ increases NRF-1 which, in turn, increases TFAM that stimulates mtDNA transcription. Estradiol can increase glucose utilization by cells and ETC activity and prevent ROS production. E2 regulate many enzymes in the TCA. E2, estradiol; mtDNA, mitochondrial DNA; SIRT3, Sirtuin 3; PGC-1α, Peroxisome proliferator-activated receptor gamma, coactivator-1 alpha; NRF1, Nuclear respiratory factor −1; ERβ, Estrogen receptor beta; TFAM, Transcription factor A, mitochondrial; TCA, tricarboxylic acid cycle; ETC, Electron transport chain.

A decline in estradiol (E2) levels leads to significant reductions in mitochondrial function, resulting in oxidative stress and impaired cerebral bioenergetics. Preclinical studies have shown increased hippocampal Aβ accumulation under E2-deficient conditions. This phenotype is characterized by reduced maximal respiratory capacity, diminished basal oxygen consumption, and lower extracellular acidification rates—indicative of decreased lactate production and glycolytic activity (Irwin et al., 2012).

Estrogens regulate the expression and activity of key enzymes in glycolysis, including hexokinase, phosphoglucoisomerase, phosphofructokinase, aldolase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, 6-phosphofructo-2-kinase, and fructose 2,6-bisphosphatase (Lizcano and Guzman, 2014). Estrogens also enhance the expression of glucose transporters GLUT3 and GLUT4 in the brain (Stirone et al., 2005; Razmara et al., 2008). In addition, estrogenic regulation extends to enzymes of the tricarboxylic acid (TCA) cycle, such as citrate synthase, mitochondrial aconitase 2, isocitrate dehydrogenase, and succinate dehydrogenase (Nilsen et al., 2007; Alaynick, 2008; Lizcano, 2022).

6 Do GLP-1 receptor agonists influence mitochondria and Alzheimer’s disease?

Type 2 diabetes mellitus (T2DM) and AD share metabolic abnormalities, including insulin resistance, mitochondrial dysfunction, inflammation, and increased oxidative stress. Incretin-based antidiabetic therapies, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), may offer benefits for individuals at risk of neurodegeneration due to their central effects on appetite and satiety regulation via the hypothalamus (Correia et al., 2012). Beyond glucose lowering and weight reduction, GLP-1RAs have shown positive effects on cognitive dysfunction in T2DM patients (Reich and Holscher, 2022).

While GLP-1 is primarily synthesized and secreted by intestinal L-cells in response to nutrient intake, it is also produced in the brain, particularly in the nucleus of the solitary tract in the brainstem. Following the ingestion of carbohydrates and fats, GLP-1 is released and exerts multiple physiological effects essential for maintaining glucose homeostasis (Bullock et al., 1996). It promotes glucose-dependent insulin secretion from pancreatic β-cells, ensuring proportional release relative to glycemia, and concurrently inhibits glucagon secretion from α-cells, reducing hepatic glucose production. GLP-1 also delays gastric emptying, thereby moderating postprandial glycemic excursions, and enhances satiety via central nervous system (CNS) signaling, contributing to appetite suppression and weight loss (Drucker, 2006).

Metabolically, GLP-1 acts through G protein-coupled receptors to improve insulin sensitivity in muscle and adipose tissues while enhancing β-cell function by promoting proliferation and inhibiting apoptosis (see Figure 3). Additionally, GLP-1RAs exert cardiovascular benefits, including improved endothelial function, reduced blood pressure, and cardioprotection. Clinically, GLP-1RAs—such as exenatide, liraglutide, dulaglutide, semaglutide, and tirzepatide—are used to manage T2DM, mimicking endogenous GLP-1 activity. These agents not only enhance glycemic control but also promote satiety and delay gastric emptying, making them effective in treating obesity (Drucker et al., 1987; Kreymann et al., 1987; Mojsov et al., 1987; Turton et al., 1996; Baggio and Drucker, 2007). The effects of GLP-1 on different tissues have demonstrated an enhanced insulin effect on skeletal muscle through SESN2-mediated autophagy and the attenuation of IRS1 serine phosphorylation (Tian et al., 2023). In obese mouse models, liraglutide improved insulin sensitivity in visceral adipose tissue, which was associated with reduced endoplasmic reticulum stress and increased Akt phosphorylation following insulin stimulation (Jiang et al., 2018). However, regarding the proliferation of insulin-producing pancreatic beta cells, there is no consensus regarding the ability to stimulate cell proliferation. Although GLP-1 receptor agonists have been shown to induce β-cell proliferation in rodent models, particularly in young animals, this effect has not been consistently replicated in human islets, where β-cell replication capacity is markedly limited. Thus, in humans, GLP-1 action appears to be predominantly functional and anti-apoptotic rather than proliferative (Dai et al., 2017; Buteau et al., 2003).

Figure 3
www.frontiersin.org

Figure 3. GLP-1RA activation initiates a cascade of signaling events through Gαs coupling, leading to the activation of adenylyl cyclase (AC) and subsequent production of cAMP. Protein kinase A (PKA) acts as a central mediator of downstream effects, modulating various ion channels. These channels jointly regulate membrane depolarization and calcium (Ca2+) influx. Parallel signaling through Akt activates ERK 1/2, which differentiates cellular responses: nuclear translocation of ERK 1/2 leads to transcriptional activation via mTOR and CREB, while cytoplasmic activation targets specific partners. The PI3K/AKT pathway regulates cell survival and metabolism. Calcium-dependent activation of CaMKII modulates these processes, emphasizing the complexity and versatility of GLP-1R signaling. Activation of PKA increase Memory, BDNF reduce oxidative stress and synapse loss. GSK-3β reduce tau phosphorylation, Akt reduce cytotoxity and apoptosis. PI3K, phosphoinositide 3-kinase; PKA, Protein kinase A; AkT, protein kinase B; ERK, Extracellular Signal-regulated Kinase; mTOR, mammalian target of rapamycin; GSK-3β, glycogen synthase kinase-3β; CREB, cAMP response element-binding protein; BDNF, Brain-derived neurotrophic factor; CaMKII, Ca2+/calmodulin-dependent protein kinase II.

Both peripherally secreted GLP-1 and pharmacologic GLP-1RAs can cross the blood–brain barrier (BBB) or interact with circumventricular organs, suggesting that peripheral administration is sufficient to reach CNS targets. Central administration of GLP-1RAs reduces food intake, likely via GLP-1 receptor–expressing regions in the hypothalamus and brainstem (Kastin and Akerstrom, 2003), many of which are also estrogen targets (Kanoski et al., 2011), supporting a potential interaction between these systems (Miller, 2012). Substantial evidence suggests that GLP-1R signaling in the central nervous system (CNS) modulates reward-driven behavior, including food cravings and substance addiction, underscoring the broader implications of these peptides in neurobehavioral regulation (Shirazi et al., 2013; Richard et al., 2015).

Recent investigations have explored the therapeutic potential of GLP-1 in cardiovascular disease, metabolic-associated fatty liver disease, Parkinson’s disease, and AD. These multifaceted mechanisms underscore the relevance of GLP-1 in managing metabolic, cardiovascular, and neurodegenerative disorders (Cukierman-Yaffe et al., 2020; Arredouani, 2025).

The cloning and characterization of the GLP-1 receptor (GLP-1R) marked a key milestone in understanding GLP-1’s mechanisms of action. Pharmacological and molecular biology studies identified GLP-1R as a high-affinity receptor expressed across diverse tissues. As a member of the G protein–coupled receptor (GPCR) family, GLP-1R features a large extracellular domain responsible for ligand recognition and binding (Drucker and Holst, 2023).

The widespread expression of GLP-1R suggests that GLP-1 plays pleiotropic physiological roles beyond insulin secretion. In the CNS, GLP-1 has demonstrated neuroprotective effects, particularly in the hippocampus and cerebral cortex—key regions for memory and learning. These benefits include reducing neuroinflammation, improving neuronal energy homeostasis, and limiting neurodegenerative progression (Adams et al., 2018; Chang et al., 2018).

Potential mechanisms by which GLP-1RAs enhance cognition in T2DM patients include attenuation of oxidative stress, suppression of neuroinflammation, inhibition of apoptosis, reduction or prevention of Aβ accumulation, and mitigation of tau aggregation (Yaribeygi et al., 2021). Several preclinical studies have confirmed the ability of GLP-1RAs to reduce Aβ and tau deposits. Although findings in human studies have been less consistent, a pilot study reported reduced cerebrospinal fluid levels of Aβ42, and a large-scale clinical trial is currently underway to assess the efficacy of a GLP-1RA in early-stage AD patients (Crook and Edison, 2024; Cummings et al., 2025).

These pharmacological advances have reshaped the management of metabolic diseases, improving glycemic control, weight reduction, and cardiovascular outcomes. As research continues, GLP-1’s therapeutic potential in AD remains a promising frontier (Gejl et al., 2016; Du et al., 2022). Phase II clinical trial results with liraglutide support this hypothesis. In a multicenter UK study involving 204 participants randomized to liraglutide or placebo, cognitive decline in the liraglutide group was 18% slower than in the placebo group after 1 year of treatment (Femminella et al., 2019). Liraglutide may reduce neuroinflammation, decrease insulin resistance, improve neuronal communication, and limit Aβ and tau pathology.

Currently, the first randomized, double-blind phase III trial is underway to evaluate the effects of oral Semaglutide in AD prevention and progression. The EVOKE and EVOKE + trials are supported by robust preclinical evidence demonstrating GLP-1RA benefits in neurodegeneration and cognitive enhancement in T2DM patients (Akimoto et al., 2020; Cukierman-Yaffe et al., 2020; Norgaard et al., 2022).

7 Could dual agonism of estrogen and GLP-1 influence Alzheimer’s disease prevention?

The social and clinical impact of GLP-1RA therapy is reflected in the growing number of individuals using these medications. Currently, one in eight U.S. adults over the age of 18 reports having used a GLP-1 analogue (Harris, 2024). Additionally, novel combination therapies—such as Tirzepatide, which combines a GLP-1 analogue with glucose-dependent insulinotropic polypeptide (GIP)-are rapidly gaining traction, and it is expected that new formulations will continue to emerge, incorporating peptides capable of modulating metabolism and thermogenesis (Jastreboff et al., 2022; Rosenstock et al., 2023; Loomba et al., 2024).

Despite their widespread use, certain aspects of GLP-1 function, particularly its actions in the central nervous system (CNS), remain poorly understood—an important gap given the growing number of patients receiving these treatments. A key limitation of preclinical research, including GLP-1RA studies, is that most experiments are conducted in male animals. This introduces variability in pharmacodynamics, as GLP-1RA penetration into specific brain regions may differ based on sex, compound properties, and age (Borchers and Skibicka, 2025).

This raises important questions for ongoing trials such as EVOKE, which may uncover sex-specific differences and justify subsequent investigations of GLP-1 analogues in female populations. Moreover, the combined effect of GLP-1RAs with other molecules may vary depending on sex. Known polymorphisms and splice variants in ERβ could influence the efficacy of estrogen therapy in AD and may also impact GLP-1RA activity. Exploring these potential interactions could enhance our understanding of brain-targeted pharmacotherapy (Holscher, 2018; Jastreboff et al., 2022).

Sex differences in the incidence and progression of aging-related neurodegenerative diseases, particularly Alzheimer’s disease, are well established and globally consistent. In the United States, although men have higher age-adjusted mortality rates for 8 of the 10 leading causes of death, AD is a notable exception: women experience higher prevalence and AD-specific mortality, making it the only major cause of death more common in women (Budreviciute et al., 2020). This trend extends beyond the U.S., with higher AD burden reported among women in Europe, the United Kingdom, Japan, and other regions (Benziger et al., 2016).

Today, nearly two-thirds of patients receiving medical care for AD are women. This statistic reflects both a higher age-adjusted incidence of AD and longer life expectancy among women (Report, 2024). However, this female predominance appears paradoxical given the greater prevalence of classical AD risk factors-such as cardiovascular and metabolic diseases-among men. One explanation involves survival bias: men with high AD risk may die earlier from cardiovascular events, precluding the clinical manifestation of dementia. Sociocultural factors, such as unequal access to education in the 20th century (a known protective factor), may also play a role.

From a biological standpoint, several hypotheses have been proposed to explain female susceptibility to AD. Mitochondrial dysfunction plays a central role in AD pathophysiology, but sex differences in mitochondrial function remain poorly defined. Experimental models have shown that male and female animals differ in mitochondrial substrate utilization under stress conditions, though findings vary by context. For instance, in 3xTg-AD mice, sex-specific alterations in brain bioenergetics have been observed: females showed impaired complex I activity in synaptic cortical mitochondria, while non-synaptic mitochondria exhibited enhanced complex II–mediated respiration (Stojakovic et al., 2021).

In developmental neurobiology, Arnold proposed three categories of sex differentiation mechanisms: (1) organizational differences driven by fetal hormonal exposure; (2) activational differences induced by the adult hormonal environment; and (3) genetic differences linked to chromosomal content (Arnold, 2022). Studies using transgenic hAPP mouse models have shown that XY animals exhibit more severe clinical courses and earlier mortality compared to XX animals, independent of gonadal sex. This suggests a protective role of the second X chromosome (Davis et al., 2020), reinforcing the need to consider both genetic and hormonal factors when designing targeted therapies, including those involving hormonal agonists and estrogens for AD prevention (Lopez-Lee et al., 2024).

The beneficial effects of estrogens and GLP-1 agonists observed in other metabolic diseases raise the possibility that their combined use could also prevent or delay the onset of Alzheimer’s disease. A dual GLP-1-estrogen conjugate (GE) designed to selectively deliver estrogen to GLP-1R + cells induced substantial weight loss in mice without evidence of systemic estrogenic effects, as assessed by uterine weight and growth of estrogen-dependent breast cancer xenografts (Finan et al., 2012). Genetic studies in mice suggested that these effects were mediated by CNS GLP-1Rs, with increased expression of POMC and leptin receptors in the arcuate nucleus (Kanoski et al., 2011). Selective estrogen delivery to β-cells via a GE conjugate improved viability in both human and murine β-cells, again without systemic estrogen exposure (Sachs et al., 2020).

In another preclinical study, GE demonstrated superior metabolic effects compared to GLP-1-GIP or GLP-1-GIP-glucagon multiagonist therapies in models of polycystic ovary syndrome (PCOS), a condition frequently associated with obesity and insulin resistance. Chronic GE administration in female mice with PCOS significantly improved metabolic profiles, outperforming individual agonists. In the PWA model, GE suppressed hypothalamic expression of BCAP31, a pro-apoptotic protein, and promoted proteins associated with autophagy-critical processes for neuronal function and energy homeostasis. Altered CAMKII expression, which regulates orexigenic neuropeptides like NPY, also reflected compensatory adaptation to weight loss (Sanchez-Garrido et al., 2024).

Previous studies in obese rodents and diet-induced obesity models have shown that GE’s primary site of action is central, particularly within hypothalamic regions such as the supramammillary nucleus, lateral hypothalamus, and the nucleus of the solitary tract (Tiano et al., 2015). This therapeutic strategy-combining GLP-1 and estrogen receptor activation—was developed to enhance metabolic benefits while limiting systemic estrogen exposure, thereby minimizing reproductive and oncogenic risks. Data confirm that this approach enables tissue-specific action in GLP–1R–expressing regions, avoiding adverse effects in reproductive organs (Vogel et al., 2016).

Proteomic analyses of the hypothalamus following GE treatment revealed downregulation of inflammation-, apoptosis-, and immune-related proteins, and upregulation of pathways related to autophagy, vesicular transport, and intracellular signaling. These changes may help restore central energy homeostasis and explain the marked weight loss observed even at moderate GE doses (Schwenk et al., 2015).

8 Conclusion

Alzheimer’s disease remains a complex neurodegenerative disorder with multifactorial origins, including amyloid accumulation, tau pathology, insulin resistance, mitochondrial dysfunction, and chronic inflammation. The evidence reviewed herein underscores the critical role of estrogens in maintaining neuronal homeostasis, particularly through their effects on mitochondrial efficiency, antioxidant defense, and synaptic resilience. In parallel, GLP-1 receptor agonists have demonstrated neuroprotective actions beyond their established metabolic benefits, offering a promising avenue for cognitive preservation in at-risk individuals.

The convergence of estrogen and GLP-1 signaling on metabolic and neuroinflammatory pathways supports the rationale for dual-targeted interventions. Preclinical models using GLP-1–estrogen conjugates have shown superior outcomes in metabolic regulation, neuronal viability, and hypothalamic signaling, with reduced systemic estrogenic effects. These findings open a new frontier in personalized neuroendocrine therapy, particularly relevant for postmenopausal women, who bear a disproportionate burden of AD and are often underrepresented in clinical trials.

Future research must prioritize the inclusion of sex as a biological variable, explore differential receptor expression and function, and validate the safety and efficacy of dual agonist strategies in humans. As large-scale trials like EVOKE and EVOKE + unfold, integrating insights from estrogen biology could enhance the impact of GLP-1–based therapies in neurodegenerative disease. Ultimately, a deeper understanding of hormone–metabolism interactions may unlock novel, sex-specific strategies for the prevention of Alzheimer’s disease.

Author contributions

FL: Software, Supervision, Methodology, Data curation, Conceptualization, Validation, Investigation, Formal Analysis, Funding acquisition, Resources, Writing – review and editing, Visualization, Project administration, Writing – original draft. DS: Conceptualization, Methodology, Visualization, Supervision, Writing – review and editing, Software. EA: Methodology, Writing – review and editing, Validation, Investigation, Software, Data curation.

Funding

The author(s) declare that no financial support was received for the research and/or publication of this 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.

Generative AI statement

The author(s) declare that Generative AI was used in the creation of this manuscript. We used generative AI in order to perfor translation.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

Abdelsalam, S. A., Renu, K., Zahra, H. A., Abdallah, B. M., Ali, E. M., Veeraraghavan, V. P., et al. (2023). Polyphenols mediate neuroprotection in cerebral ischemic stroke-an update. Nutrients 15 (5), 1107. doi:10.3390/nu15051107

PubMed Abstract | CrossRef Full Text | Google Scholar

Adams, J. M., Pei, H., Sandoval, D. A., Seeley, R. J., Chang, R. B., Liberles, S. D., et al. (2018). Liraglutide modulates appetite and body weight through glucagon-like peptide 1 receptor-expressing glutamatergic neurons. Diabetes 67 (8), 1538–1548. doi:10.2337/db17-1385

PubMed Abstract | CrossRef Full Text | Google Scholar

Akimoto, H., Negishi, A., Oshima, S., Wakiyama, H., Okita, M., Horii, N., et al. (2020). Antidiabetic drugs for the risk of alzheimer disease in patients with type 2 DM using FAERS. Am. J. Alzheimers Dis. Other Demen 35, 1533317519899546. doi:10.1177/1533317519899546

PubMed Abstract | CrossRef Full Text | Google Scholar

Alaynick, W. A. (2008). Nuclear receptors, mitochondria and lipid metabolism. Mitochondrion 8 (4), 329–337. doi:10.1016/j.mito.2008.02.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Aranda, A., and Pascual, A. (2001). Nuclear hormone receptors and gene expression. Physiol. Rev. 81 (3), 1269–1304. doi:10.1152/physrev.2001.81.3.1269

PubMed Abstract | CrossRef Full Text | Google Scholar

Arjmand, S., Ilaghi, M., Sisakht, A. K., Guldager, M. B., Wegener, G., Landau, A. M., et al. (2024). Regulation of mitochondrial dysfunction by estrogens and estrogen receptors in Alzheimer's disease: a focused review. Basic Clin. Pharmacol. Toxicol. 135 (2), 115–132. doi:10.1111/bcpt.14035

PubMed Abstract | CrossRef Full Text | Google Scholar

Arnold, A. P. (2022). Integrating sex chromosome and endocrine theories to improve teaching of sexual differentiation. Cold Spring Harb. Perspect. Biol. 14 (9), a039057. doi:10.1101/cshperspect.a039057

PubMed Abstract | CrossRef Full Text | Google Scholar

Arredouani, A. (2025). GLP-1 receptor agonists, are we witnessing the emergence of a paradigm shift for neuro-cardio-metabolic disorders? Pharmacol. Ther. 269, 108824. doi:10.1016/j.pharmthera.2025.108824

PubMed Abstract | CrossRef Full Text | Google Scholar

Azcoitia, I., Sierra, A., Veiga, S., Honda, S., Harada, N., and Garcia-Segura, L. M. (2001). Brain aromatase is neuroprotective. J. Neurobiol. 47 (4), 318–329. doi:10.1002/neu.1038

PubMed Abstract | CrossRef Full Text | Google Scholar

Baggio, L. L., and Drucker, D. J. (2007). Biology of incretins: GLP-1 and GIP. Gastroenterology 132 (6), 2131–2157. doi:10.1053/j.gastro.2007.03.054

PubMed Abstract | CrossRef Full Text | Google Scholar

Bai, R., Guo, J., Ye, X. Y., Xie, Y., and Xie, T. (2022). Oxidative stress: the core pathogenesis and mechanism of Alzheimer's disease. Ageing Res. Rev. 77, 101619. doi:10.1016/j.arr.2022.101619

PubMed Abstract | CrossRef Full Text | Google Scholar

Baloyannis, S. J., Mavroudis, I., Baloyannis, I. S., and Costa, V. G. (2016). Mammillary bodies in Alzheimer's disease: a golgi and electron microscope study. Am. J. Alzheimers Dis. Other Demen 31 (3), 247–256. doi:10.1177/1533317515602548

PubMed Abstract | CrossRef Full Text | Google Scholar

Baloyannis, S. J., Mavroudis, I., Mitilineos, D., Baloyannis, I. S., and Costa, V. G. (2015). The hypothalamus in Alzheimer's disease: a Golgi and electron microscope study. Am. J. Alzheimers Dis. Other Demen 30 (5), 478–487. doi:10.1177/1533317514556876

PubMed Abstract | CrossRef Full Text | Google Scholar

Bassil, F., Fernagut, P. O., Bezard, E., and Meissner, W. G. (2014). Insulin, IGF-1 and GLP-1 signaling in neurodegenerative disorders: targets for disease modification? Prog. Neurobiol. 118, 1–18. doi:10.1016/j.pneurobio.2014.02.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Benziger, C. P., Roth, G. A., and Moran, A. E. (2016). The global burden of disease study and the preventable burden of NCD. Glob. Heart 11 (4), 393–397. doi:10.1016/j.gheart.2016.10.024

PubMed Abstract | CrossRef Full Text | Google Scholar

Bernabe-Ortiz, A., and Carrillo-Larco, R. M. (2022). Urbanization, altitude and cardiovascular risk. Glob. Heart 17 (1), 42. doi:10.5334/gh.1130

PubMed Abstract | CrossRef Full Text | Google Scholar

Blakemore, J., and Naftolin, F. (2016). Aromatase: contributions to physiology and disease in women and men. Physiol. (Bethesda) 31 (4), 258–269. doi:10.1152/physiol.00054.2015

PubMed Abstract | CrossRef Full Text | Google Scholar

Borchers, S., and Skibicka, K. P. (2025). GLP-1 and its analogs: does sex matter? Endocrinology 166 (2), bqae165. doi:10.1210/endocr/bqae165

PubMed Abstract | CrossRef Full Text | Google Scholar

Brann, D. W., Lu, Y., Wang, J., Sareddy, G. R., Pratap, U. P., Zhang, Q., et al. (2022). Brain-derived estrogen and neurological disorders. Biol. (Basel) 11 (12), 1698. doi:10.3390/biology11121698

PubMed Abstract | CrossRef Full Text | Google Scholar

Brewer, G. J., Herrera, R. A., Philipp, S., Sosna, J., Reyes-Ruiz, J. M., and Glabe, C. G. (2020). Age-related intraneuronal aggregation of amyloid-beta in endosomes, mitochondria, autophagosomes, and lysosomes. J. Alzheimers Dis. 73 (1), 229–246. doi:10.3233/JAD-190835

PubMed Abstract | CrossRef Full Text | Google Scholar

Budreviciute, A., Damiati, S., Sabir, D. K., Onder, K., Schuller-Goetzburg, P., Plakys, G., et al. (2020). Management and prevention strategies for non-communicable diseases (NCDs) and their risk factors. Front. Public Health 8, 574111. doi:10.3389/fpubh.2020.574111

PubMed Abstract | CrossRef Full Text | Google Scholar

Bullock, B. P., Heller, R. S., and Habener, J. F. (1996). Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology 137 (7), 2968–2978. doi:10.1210/endo.137.7.8770921

PubMed Abstract | CrossRef Full Text | Google Scholar

Buteau, J., Foisy, S., Joly, E., and Prentki, M. (2003). Glucagon-like peptide 1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor. Diabetes 52 (1), 124–132. doi:10.2337/diabetes.52.1.124

PubMed Abstract | CrossRef Full Text | Google Scholar

Chang, C. C., Lin, T. C., Ho, H. L., Kuo, C. Y., Li, H. H., Korolenko, T. A., et al. (2018). GLP-1 analogue liraglutide attenuates mutant huntingtin-induced neurotoxicity by restoration of neuronal insulin signaling. Int. J. Mol. Sci. 19 (9), 2505. doi:10.3390/ijms19092505

PubMed Abstract | CrossRef Full Text | Google Scholar

Correia, S. C., Santos, R. X., Carvalho, C., Cardoso, S., Candeias, E., Santos, M. S., et al. (2012). Insulin signaling, glucose metabolism and mitochondria: major players in Alzheimer's disease and diabetes interrelation. Brain Res. 1441, 64–78. doi:10.1016/j.brainres.2011.12.063

PubMed Abstract | CrossRef Full Text | Google Scholar

Craft, S., and Watson, G. S. (2004). Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol. 3 (3), 169–178. doi:10.1016/S1474-4422(04)00681-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Crook, H., and Edison, P. (2024). Incretin mimetics as potential disease modifying treatment for Alzheimer's disease. J. Alzheimers Dis. 101 (s1), S357–S370. doi:10.3233/JAD-240730

PubMed Abstract | CrossRef Full Text | Google Scholar

Cukierman-Yaffe, T., Gerstein, H. C., Colhoun, H. M., Diaz, R., Garcia-Perez, L. E., Lakshmanan, M., et al. (2020). Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial. Lancet Neurol. 19 (7), 582–590. doi:10.1016/S1474-4422(20)30173-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Cummings, J. L., Atri, A., Feldman, H. H., Hansson, O., Sano, M., Knop, F. K., et al. (2025). Evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer's disease. Alzheimers Res. Ther. 17 (1), 14. doi:10.1186/s13195-024-01666-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Dai, C., Hang, Y., Shostak, A., Poffenberger, G., Hart, N., Prasad, N., et al. (2017). Age-dependent human beta cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling. J. Clin. Invest 127 (10), 3835–3844. doi:10.1172/JCI91761

PubMed Abstract | CrossRef Full Text | Google Scholar

Davis, E. J., Broestl, L., Abdulai-Saiku, S., Worden, K., Bonham, L. W., Minones-Moyano, E., et al. (2020). A second X chromosome contributes to resilience in a mouse model of Alzheimer's disease. Sci. Transl. Med. 12 (558), eaaz5677. doi:10.1126/scitranslmed.aaz5677

PubMed Abstract | CrossRef Full Text | Google Scholar

Demers-Lamarche, J., Guillebaud, G., Tlili, M., Todkar, K., Belanger, N., Grondin, M., et al. (2016). Loss of mitochondrial function impairs lysosomes. J. Biol. Chem. 291 (19), 10263–10276. doi:10.1074/jbc.M115.695825

PubMed Abstract | CrossRef Full Text | Google Scholar

Drucker, D. J. (2006). The biology of incretin hormones. Cell Metab. 3 (3), 153–165. doi:10.1016/j.cmet.2006.01.004

PubMed Abstract | CrossRef Full Text | Google Scholar

Drucker, D. J., and Holst, J. J. (2023). The expanding incretin universe: from basic biology to clinical translation. Diabetologia 66 (10), 1765–1779. doi:10.1007/s00125-023-05906-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Drucker, D. J., Philippe, J., Mojsov, S., Chick, W. L., and Habener, J. F. (1987). Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc. Natl. Acad. Sci. U. S. A. 84 (10), 3434–3438. doi:10.1073/pnas.84.10.3434

PubMed Abstract | CrossRef Full Text | Google Scholar

Du, H., Guo, L., Yan, S., Sosunov, A. A., McKhann, G. M., and Yan, S. S. (2010). Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model. Proc. Natl. Acad. Sci. U. S. A. 107 (43), 18670–18675. doi:10.1073/pnas.1006586107

PubMed Abstract | CrossRef Full Text | Google Scholar

Du, H., Meng, X., Yao, Y., and Xu, J. (2022). The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer's disease. Front. Endocrinol. (Lausanne) 13, 1033479. doi:10.3389/fendo.2022.1033479

PubMed Abstract | CrossRef Full Text | Google Scholar

Elson, J. L., Herrnstadt, C., Preston, G., Thal, L., Morris, C. M., Edwardson, J. A., et al. (2006). Does the mitochondrial genome play a role in the etiology of Alzheimer's disease? Hum. Genet. 119 (3), 241–254. doi:10.1007/s00439-005-0123-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Femminella, G. D., Frangou, E., Love, S. B., Busza, G., Holmes, C., Ritchie, C., et al. (2019). Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study). Trials 20 (1), 191. doi:10.1186/s13063-019-3259-x

PubMed Abstract | CrossRef Full Text | Google Scholar

Fernandez-Mosquera, L., Diogo, C. V., Yambire, K. F., Santos, G. L., Luna Sanchez, M., Benit, P., et al. (2017). Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis. Sci. Rep. 7, 45076. doi:10.1038/srep45076

PubMed Abstract | CrossRef Full Text | Google Scholar

Finan, B., Yang, B., Ottaway, N., Stemmer, K., Muller, T. D., Yi, C. X., et al. (2012). Targeted estrogen delivery reverses the metabolic syndrome. Nat. Med. 18 (12), 1847–1856. doi:10.1038/nm.3009

PubMed Abstract | CrossRef Full Text | Google Scholar

Florian, H., Wang, D., Arnold, S. E., Boada, M., Guo, Q., Jin, Z., et al. (2023). Tilavonemab in early Alzheimer's disease: results from a phase 2, randomized, double-blind study. Brain 146 (6), 2275–2284. doi:10.1093/brain/awad024

PubMed Abstract | CrossRef Full Text | Google Scholar

Frick, K. M., Kim, J., Tuscher, J. J., and Fortress, A. M. (2015). Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents. Learn Mem. 22 (9), 472–493. doi:10.1101/lm.037267.114

PubMed Abstract | CrossRef Full Text | Google Scholar

Gejl, M., Gjedde, A., Egefjord, L., Moller, A., Hansen, S. B., Vang, K., et al. (2016). In Alzheimer's disease, 6-month treatment with GLP-1 analog prevents decline of brain glucose metabolism: randomized, placebo-controlled, double-blind clinical trial. Front. Aging Neurosci. 8, 108. doi:10.3389/fnagi.2016.00108

PubMed Abstract | CrossRef Full Text | Google Scholar

Gillies, G. E., and McArthur, S. (2010). Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines. Pharmacol. Rev. 62 (2), 155–198. doi:10.1124/pr.109.002071

PubMed Abstract | CrossRef Full Text | Google Scholar

Grimm, M. O. W., Michaelson, D. M., and Hartmann, T. (2017). Omega-3 fatty acids, lipids, and apoE lipidation in Alzheimer's disease: a rationale for multi-nutrient dementia prevention. J. Lipid Res. 58 (11), 2083–2101. doi:10.1194/jlr.R076331

PubMed Abstract | CrossRef Full Text | Google Scholar

Guo, J. L., Braun, D., Fitzgerald, G. A., Hsieh, Y. T., Rouge, L., Litvinchuk, A., et al. (2025). Decreased lipidated ApoE-receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes. Cell 188 (1), 187–206.e26. doi:10.1016/j.cell.2024.10.027

PubMed Abstract | CrossRef Full Text | Google Scholar

Haas, E., Bhattacharya, I., Brailoiu, E., Damjanovic, M., Brailoiu, G. C., Gao, X., et al. (2009). Regulatory role of G protein-coupled estrogen receptor for vascular function and obesity. Circ. Res. 104 (3), 288–291. doi:10.1161/CIRCRESAHA.108.190892

PubMed Abstract | CrossRef Full Text | Google Scholar

Han, X. (2005). Lipid alterations in the earliest clinically recognizable stage of Alzheimer's disease: implication of the role of lipids in the pathogenesis of Alzheimer's disease. Curr. Alzheimer Res. 2 (1), 65–77. doi:10.2174/1567205052772786

PubMed Abstract | CrossRef Full Text | Google Scholar

Harris, E. (2024). Poll: roughly 12% of US adults have used a GLP-1 drug, even if unaffordable. JAMA 332 (1), 8. doi:10.1001/jama.2024.10333

PubMed Abstract | CrossRef Full Text | Google Scholar

Hauser, P. S., Narayanaswami, V., and Ryan, R. O. (2011). Apolipoprotein E: from lipid transport to neurobiology. Prog. Lipid Res. 50 (1), 62–74. doi:10.1016/j.plipres.2010.09.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Hernandez-Rodriguez, M., Clemente, C. F., Macias-Perez, M. E., Rodriguez-Fonseca, R. A., Vazquez, M. I. N., Martinez, J., et al. (2022). Contribution of hyperglycemia-induced changes in microglia to Alzheimer's disease pathology. Pharmacol. Rep. 74 (5), 832–846. doi:10.1007/s43440-022-00405-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Hestiantoro, A., and Swaab, D. F. (2004). Changes in estrogen receptor-alpha and -beta in the infundibular nucleus of the human hypothalamus are related to the occurrence of Alzheimer's disease neuropathology. J. Clin. Endocrinol. Metab. 89 (4), 1912–1925. doi:10.1210/jc.2003-030862

PubMed Abstract | CrossRef Full Text | Google Scholar

Hewitt, S. C., Winuthayanon, W., Lierz, S. L., Hamilton, K. J., Donoghue, L. J., Ramsey, J. T., et al. (2017). Role of ERα in mediating female uterine transcriptional responses to IGF1. Endocrinology 158 (8), 2427–2435. doi:10.1210/en.2017-00349

PubMed Abstract | CrossRef Full Text | Google Scholar

Holscher, C. (2018). Novel dual GLP-1/GIP receptor agonists show neuroprotective effects in Alzheimer's and Parkinson's disease models. Neuropharmacology 136 (Pt B), 251–259. doi:10.1016/j.neuropharm.2018.01.040

PubMed Abstract | CrossRef Full Text | Google Scholar

Houlden, H., Crook, R., Backhovens, H., Prihar, G., Baker, M., Hutton, M., et al. (1998). ApoE genotype is a risk factor in nonpresenilin early-onset alzheimer's disease families. Am. J. Med. Genet. 81 (1), 117–121. doi:10.1002/(sici)1096-8628(19980207)81:1<117::aid-ajmg19>3.0.co;2-m

PubMed Abstract | CrossRef Full Text | Google Scholar

Huang, Y., and Mahley, R. W. (2014). Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases. Neurobiol. Dis. 72 Pt A, 3–12. doi:10.1016/j.nbd.2014.08.025

PubMed Abstract | CrossRef Full Text | Google Scholar

Irwin, R. W., Yao, J., To, J., Hamilton, R. T., Cadenas, E., and Brinton, R. D. (2012). Selective oestrogen receptor modulators differentially potentiate brain mitochondrial function. J. Neuroendocrinol. 24 (1), 236–248. doi:10.1111/j.1365-2826.2011.02251.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Jackson, R. J., Hyman, B. T., and Serrano-Pozo, A. (2024). Multifaceted roles of APOE in Alzheimer disease. Nat. Rev. Neurol. 20 (8), 457–474. doi:10.1038/s41582-024-00988-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Jastreboff, A. M., Aronne, L. J., Ahmad, N. N., Wharton, S., Connery, L., Alves, B., et al. (2022). Tirzepatide once weekly for the treatment of obesity. N. Engl. J. Med. 387 (3), 205–216. doi:10.1056/NEJMoa2206038

PubMed Abstract | CrossRef Full Text | Google Scholar

Jellinger, K. A. (2024). Depression and anxiety in multiple sclerosis. Review of a fatal combination. J. Neural Transm. (Vienna) 131 (8), 847–869. doi:10.1007/s00702-024-02792-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Jiang, Y., Wang, Z., Ma, B., Fan, L., Yi, N., Lu, B., et al. (2018). GLP-1 improves adipocyte insulin sensitivity following induction of endoplasmic reticulum stress. Front. Pharmacol. 9, 1168. doi:10.3389/fphar.2018.01168

PubMed Abstract | CrossRef Full Text | Google Scholar

Johri, A., Roncati, L., and Lizcano, F. (2024). Editorial: endocrine disruptors and diseases of brain and mind: past and prelude. Front. Endocrinol. (Lausanne) 15, 1362519. doi:10.3389/fendo.2024.1362519

PubMed Abstract | CrossRef Full Text | Google Scholar

Joshi, A. U., Saw, N. L., Shamloo, M., and Mochly-Rosen, D. (2018). Drp1/Fis1 interaction mediates mitochondrial dysfunction, bioenergetic failure and cognitive decline in Alzheimer's disease. Oncotarget 9 (5), 6128–6143. doi:10.18632/oncotarget.23640

PubMed Abstract | CrossRef Full Text | Google Scholar

Kanoski, S. E., Fortin, S. M., Arnold, M., Grill, H. J., and Hayes, M. R. (2011). Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4. Endocrinology 152 (8), 3103–3112. doi:10.1210/en.2011-0174

PubMed Abstract | CrossRef Full Text | Google Scholar

Kapogiannis, D., Mustapic, M., Shardell, M. D., Berkowitz, S. T., Diehl, T. C., Spangler, R. D., et al. (2019). Association of extracellular vesicle biomarkers with alzheimer disease in the Baltimore longitudinal study of aging. JAMA Neurol. 76 (11), 1340–1351. doi:10.1001/jamaneurol.2019.2462

PubMed Abstract | CrossRef Full Text | Google Scholar

Karim, H., Kim, S. H., Lapato, A. S., Yasui, N., Katzenellenbogen, J. A., and Tiwari-Woodruff, S. K. (2018). Increase in chemokine CXCL1 by ERβ ligand treatment is a key mediator in promoting axon myelination. Proc. Natl. Acad. Sci. U. S. A. 115 (24), 6291–6296. doi:10.1073/pnas.1721732115

PubMed Abstract | CrossRef Full Text | Google Scholar

Kastin, A. J., and Akerstrom, V. (2003). Entry of exendin-4 into brain is rapid but may be limited at high doses. Int. J. Obes. Relat. Metab. Disord. 27 (3), 313–318. doi:10.1038/sj.ijo.0802206

PubMed Abstract | CrossRef Full Text | Google Scholar

Kellar, D., and Craft, S. (2020). Brain insulin resistance in Alzheimer's disease and related disorders: mechanisms and therapeutic approaches. Lancet Neurol. 19 (9), 758–766. doi:10.1016/S1474-4422(20)30231-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Kelly, M. J., and Ronnekleiv, O. K. (2012). Membrane-initiated actions of estradiol that regulate reproduction, energy balance and body temperature. Front. Neuroendocrinol. 33 (4), 376–387. doi:10.1016/j.yfrne.2012.07.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Kim, C. K., Torcaso, A., Asimes, A., Chung, W. C. J., and Pak, T. R. (2018). Structural and functional characteristics of oestrogen receptor beta splice variants: implications for the ageing brain. J. Neuroendocrinol. 30 (2). doi:10.1111/jne.12488

PubMed Abstract | CrossRef Full Text | Google Scholar

Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., and Lamb, B. T. (2018). Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement. (N Y) 4, 575–590. doi:10.1016/j.trci.2018.06.014

PubMed Abstract | CrossRef Full Text | Google Scholar

Knopman, D. S., Amieva, H., Petersen, R. C., Chetelat, G., Holtzman, D. M., Hyman, B. T., et al. (2021). Alzheimer disease. Nat. Rev. Dis. Prim. 7 (1), 33. doi:10.1038/s41572-021-00269-y

PubMed Abstract | CrossRef Full Text | Google Scholar

Kober, D. L., and Brett, T. J. (2017). TREM2-Ligand interactions in Health and disease. J. Mol. Biol. 429 (11), 1607–1629. doi:10.1016/j.jmb.2017.04.004

PubMed Abstract | CrossRef Full Text | Google Scholar

Kreymann, B., Williams, G., Ghatei, M. A., and Bloom, S. R. (1987). Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet 2 (8571), 1300–1304. doi:10.1016/s0140-6736(87)91194-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Kruijver, F. P., Balesar, R., Espila, A. M., Unmehopa, U. A., and Swaab, D. F. (2003). Estrogen-receptor-beta distribution in the human hypothalamus: similarities and differences with ER alpha distribution. J. Comp. Neurol. 466 (2), 251–277. doi:10.1002/cne.10899

PubMed Abstract | CrossRef Full Text | Google Scholar

Laflamme, N., Nappi, R. E., Drolet, G., Labrie, C., and Rivest, S. (1998). Expression and neuropeptidergic characterization of estrogen receptors (ERalpha and ERbeta) throughout the rat brain: anatomical evidence of distinct roles of each subtype. J. Neurobiol. 36 (3), 357–378. doi:10.1002/(sici)1097-4695(19980905)36:3<357::aid-neu5>3.0.co;2-v

PubMed Abstract | CrossRef Full Text | Google Scholar

Lane, C. A., Hardy, J., and Schott, J. M. (2018). Alzheimer's disease. Eur. J. Neurol. 25 (1), 59–70. doi:10.1111/ene.13439

PubMed Abstract | CrossRef Full Text | Google Scholar

Lane, D. J. R., Ayton, S., and Bush, A. I. (2018). Iron and Alzheimer's disease: an update on emerging mechanisms. J. Alzheimers Dis. 64 (s1), S379–S395. doi:10.3233/JAD-179944

PubMed Abstract | CrossRef Full Text | Google Scholar

Leclere, R., Torregrosa-Munumer, R., Kireev, R., Garcia, C., Vara, E., Tresguerres, J. A., et al. (2013). Effect of estrogens on base excision repair in brain and liver mitochondria of aged female rats. Biogerontology 14 (4), 383–394. doi:10.1007/s10522-013-9431-x

PubMed Abstract | CrossRef Full Text | Google Scholar

Liang, Y., Dore, V., Rowe, C. C., and Krishnadas, N. (2024). Clinical evidence for GLP-1 receptor agonists in Alzheimer's disease: a systematic review. J. Alzheimers Dis. Rep. 8 (1), 777–789. doi:10.3233/ADR-230181

PubMed Abstract | CrossRef Full Text | Google Scholar

Livingston, G., Huntley, J., Sommerlad, A., Ames, D., Ballard, C., Banerjee, S., et al. (2020). Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396 (10248), 413–446. doi:10.1016/S0140-6736(20)30367-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Lizcano, F. (2022). Roles of estrogens, estrogen-like compounds, and endocrine disruptors in adipocytes. Front. Endocrinol. (Lausanne) 13, 921504. doi:10.3389/fendo.2022.921504

PubMed Abstract | CrossRef Full Text | Google Scholar

Lizcano, F., and Guzman, G. (2014). Estrogen deficiency and the origin of obesity during menopause. Biomed. Res. Int. 2014, 757461. doi:10.1155/2014/757461

PubMed Abstract | CrossRef Full Text | Google Scholar

Lonard, D. M., and O'Malley, B. W. (2006). The expanding cosmos of nuclear receptor coactivators. Cell 125 (3), 411–414. doi:10.1016/j.cell.2006.04.021

PubMed Abstract | CrossRef Full Text | Google Scholar

Long, J., He, P., Shen, Y., and Li, R. (2012). New evidence of mitochondria dysfunction in the female Alzheimer's disease brain: deficiency of estrogen receptor-β. J. Alzheimers Dis. 30 (3), 545–558. doi:10.3233/JAD-2012-120283

PubMed Abstract | CrossRef Full Text | Google Scholar

Loomba, R., Hartman, M. L., Lawitz, E. J., Vuppalanchi, R., Boursier, J., Bugianesi, E., et al. (2024). Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N. Engl. J. Med. 391 (4), 299–310. doi:10.1056/NEJMoa2401943

PubMed Abstract | CrossRef Full Text | Google Scholar

Lopez-Lee, C., Torres, E. R. S., Carling, G., and Gan, L. (2024). Mechanisms of sex differences in Alzheimer's disease. Neuron 112 (8), 1208–1221. doi:10.1016/j.neuron.2024.01.024

PubMed Abstract | CrossRef Full Text | Google Scholar

Luo, J., and Liu, D. (2020). Does GPER really function as a G protein-coupled estrogen receptor in vivo? Front. Endocrinol. (Lausanne) 11, 148. doi:10.3389/fendo.2020.00148

PubMed Abstract | CrossRef Full Text | Google Scholar

Manczak, M., Calkins, M. J., and Reddy, P. H. (2011). Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage. Hum. Mol. Genet. 20 (13), 2495–2509. doi:10.1093/hmg/ddr139

PubMed Abstract | CrossRef Full Text | Google Scholar

Marino, M., Galluzzo, P., and Ascenzi, P. (2006). Estrogen signaling multiple pathways to impact gene transcription. Curr. Genomics 7 (8), 497–508. doi:10.2174/138920206779315737

PubMed Abstract | CrossRef Full Text | Google Scholar

Matthews, J., and Gustafsson, J. A. (2003). Estrogen signaling: a subtle balance between ER alpha and ER beta. Mol. Interv. 3 (5), 281–292. doi:10.1124/mi.3.5.281

PubMed Abstract | CrossRef Full Text | Google Scholar

Mauvais-Jarvis, F., Clegg, D. J., and Hevener, A. L. (2013). The role of estrogens in control of energy balance and glucose homeostasis. Endocr. Rev. 34 (3), 309–338. doi:10.1210/er.2012-1055

PubMed Abstract | CrossRef Full Text | Google Scholar

McCullough, L. D., Blizzard, K., Simpson, E. R., Oz, O. K., and Hurn, P. D. (2003). Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection. J. Neurosci. 23 (25), 8701–8705. doi:10.1523/JNEUROSCI.23-25-08701.2003

PubMed Abstract | CrossRef Full Text | Google Scholar

McEwen, B. S., Gould, E., Orchinik, M., Weiland, N. G., and Woolley, C. S. (1995). Oestrogens and the structural and functional plasticity of neurons: implications for memory, ageing and neurodegenerative processes. Ciba Found. Symp. 191, 52–73. doi:10.1002/9780470514757.ch4

PubMed Abstract | CrossRef Full Text | Google Scholar

McEwen, B. S., and Woolley, C. S. (1994). Estradiol and progesterone regulate neuronal structure and synaptic connectivity in adult as well as developing brain. Exp. Gerontol. 29 (3-4), 431–436. doi:10.1016/0531-5565(94)90022-1

PubMed Abstract | CrossRef Full Text | Google Scholar

McGill Percy, K. C., Liu, Z., and Qi, X. (2025). Mitochondrial dysfunction in Alzheimer's disease: guiding the path to targeted therapies. Neurotherapeutics 22 (3), e00525. doi:10.1016/j.neurot.2025.e00525

PubMed Abstract | CrossRef Full Text | Google Scholar

Meyer, M. R., Prossnitz, E. R., and Barton, M. (2011). GPER/GPR30 and regulation of vascular tone and blood pressure. Immunol. Endocr. Metab. Agents Med. Chem. 11 (4), 255–261. doi:10.2174/1871522211108040255

PubMed Abstract | CrossRef Full Text | Google Scholar

Miller, V. M. (2012). In pursuit of scientific excellence: sex matters. Adv. Physiol. Educ. 36 (2), 83–84. doi:10.1152/advan.00039.2012

PubMed Abstract | CrossRef Full Text | Google Scholar

Mitra, S. W., Hoskin, E., Yudkovitz, J., Pear, L., Wilkinson, H. A., Hayashi, S., et al. (2003). Immunolocalization of estrogen receptor beta in the mouse brain: comparison with estrogen receptor alpha. Endocrinology 144 (5), 2055–2067. doi:10.1210/en.2002-221069

PubMed Abstract | CrossRef Full Text | Google Scholar

Mittal, K., and Katare, D. P. (2016). Shared links between type 2 diabetes mellitus and Alzheimer's disease: a review. Diabetes Metab. Syndr. 10 (2 Suppl. 1), S144–S149. doi:10.1016/j.dsx.2016.01.021

PubMed Abstract | CrossRef Full Text | Google Scholar

Mojsov, S., Weir, G. C., and Habener, J. F. (1987). Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J. Clin. Invest 79 (2), 616–619. doi:10.1172/JCI112855

PubMed Abstract | CrossRef Full Text | Google Scholar

Monteiro, C., Toth, B., Brunstein, F., Bobbala, A., Datta, S., Ceniceros, R., et al. (2023). Randomized phase II study of the safety and efficacy of semorinemab in participants with mild-to-moderate alzheimer disease: lauriet. Neurology 101 (14), e1391–e1401. doi:10.1212/WNL.0000000000207663

PubMed Abstract | CrossRef Full Text | Google Scholar

Montero-Odasso, M., Ismail, Z., and Livingston, G. (2020). One third of dementia cases can be prevented within the next 25 years by tackling risk factors. The case “for” and “against”. Alzheimers Res. Ther. 12 (1), 81. doi:10.1186/s13195-020-00646-x

PubMed Abstract | CrossRef Full Text | Google Scholar

Mukai, H., Kimoto, T., Hojo, Y., Kawato, S., Murakami, G., Higo, S., et al. (2010). Modulation of synaptic plasticity by brain estrogen in the hippocampus. Biochim. Biophys. Acta 1800 (10), 1030–1044. doi:10.1016/j.bbagen.2009.11.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Na, W., Lee, J. Y., Kim, W. S., Yune, T. Y., and Ju, B. G. (2015). 17β-Estradiol ameliorates tight junction disruption via repression of MMP transcription. Mol. Endocrinol. 29 (9), 1347–1361. doi:10.1210/ME.2015-1124

PubMed Abstract | CrossRef Full Text | Google Scholar

Neha, , and Parvez, S. (2023). Emerging therapeutics agents and recent advances in drug repurposing for Alzheimer's disease. Ageing Res. Rev. 85, 101815. doi:10.1016/j.arr.2022.101815

PubMed Abstract | CrossRef Full Text | Google Scholar

Neth, B. J., and Craft, S. (2017). Insulin resistance and Alzheimer's disease: bioenergetic linkages. Front. Aging Neurosci. 9, 345. doi:10.3389/fnagi.2017.00345

PubMed Abstract | CrossRef Full Text | Google Scholar

Neu, S. C., Pa, J., Kukull, W., Beekly, D., Kuzma, A., Gangadharan, P., et al. (2017). Apolipoprotein E genotype and sex risk factors for alzheimer disease: a meta-analysis. JAMA Neurol. 74 (10), 1178–1189. doi:10.1001/jamaneurol.2017.2188

PubMed Abstract | CrossRef Full Text | Google Scholar

Nilsen, J., Irwin, R. W., Gallaher, T. K., and Brinton, R. D. (2007). Estradiol in vivo regulation of brain mitochondrial proteome. J. Neurosci. 27 (51), 14069–14077. doi:10.1523/JNEUROSCI.4391-07.2007

PubMed Abstract | CrossRef Full Text | Google Scholar

Nilsson, B. O., Olde, B., and Leeb-Lundberg, L. M. (2011). G protein-coupled oestrogen receptor 1 (GPER1)/GPR30: a new player in cardiovascular and metabolic oestrogenic signalling. Br. J. Pharmacol. 163 (6), 1131–1139. doi:10.1111/j.1476-5381.2011.01235.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Norgaard, C. H., Friedrich, S., Hansen, C. T., Gerds, T., Ballard, C., Moller, D. V., et al. (2022). Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia: data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers. Alzheimers Dement. (N Y) 8 (1), e12268. doi:10.1002/trc2.12268

PubMed Abstract | CrossRef Full Text | Google Scholar

Notkola, I. L., Sulkava, R., Pekkanen, J., Erkinjuntti, T., Ehnholm, C., Kivinen, P., et al. (1998). Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease. Neuroepidemiology 17 (1), 14–20. doi:10.1159/000026149

PubMed Abstract | CrossRef Full Text | Google Scholar

OMS (2021). Global status report on the public health response to dementia: executive summary. Editor D.o.M.H.a.S.U.W.H. Geneva: World Health Organization.

Google Scholar

Paidi, R. K., Nthenge-Ngumbau, D. N., Singh, R., Kankanala, T., Mehta, H., and Mohanakumar, K. P. (2015). Mitochondrial deficits accompany cognitive decline following single bilateral intracerebroventricular streptozotocin. Curr. Alzheimer Res. 12 (8), 785–795. doi:10.2174/1567205012666150710112618

PubMed Abstract | CrossRef Full Text | Google Scholar

Peggion, C., Cali, T., and Brini, M. (2024). Mitochondria dysfunction and neuroinflammation in neurodegeneration: who comes first? Antioxidants (Basel) 13 (2), 240. doi:10.3390/antiox13020240

PubMed Abstract | CrossRef Full Text | Google Scholar

Penke, B., Paragi, G., Gera, J., Berkecz, R., Kovacs, Z., Crul, T., et al. (2018). The role of lipids and membranes in the pathogenesis of Alzheimer's disease: a comprehensive view. Curr. Alzheimer Res. 15 (13), 1191–1212. doi:10.2174/1567205015666180911151716

PubMed Abstract | CrossRef Full Text | Google Scholar

Peralta, M., and Lizcano, F. (2024). Endocrine disruptors and metabolic changes: impact on puberty control. Endocr. Pract. 30 (4), 384–397. doi:10.1016/j.eprac.2024.01.006

PubMed Abstract | CrossRef Full Text | Google Scholar

Razmara, A., Sunday, L., Stirone, C., Wang, X. B., Krause, D. N., Duckles, S. P., et al. (2008). Mitochondrial effects of estrogen are mediated by estrogen receptor alpha in brain endothelial cells. J. Pharmacol. Exp. Ther. 325 (3), 782–790. doi:10.1124/jpet.107.134072

PubMed Abstract | CrossRef Full Text | Google Scholar

Reich, N., and Holscher, C. (2022). The neuroprotective effects of glucagon-like peptide 1 in Alzheimer's and Parkinson's disease: an in-depth review. Front. Neurosci. 16, 970925. doi:10.3389/fnins.2022.970925

PubMed Abstract | CrossRef Full Text | Google Scholar

Reiman, E. M., Arboleda-Velasquez, J. F., Quiroz, Y. T., Huentelman, M. J., Beach, T. G., Caselli, R. J., et al. (2020). Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat. Commun. 11 (1), 667. doi:10.1038/s41467-019-14279-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Report, A.S.A.(2024). 2024 Alzheimer’s disease facts and figures. Alzheimers Dement. 20(5). 3708–3821. doi:10.1002/alz.13809

PubMed Abstract | CrossRef Full Text | Google Scholar

Richard, J. E., Anderberg, R. H., Goteson, A., Gribble, F. M., Reimann, F., and Skibicka, K. P. (2015). Activation of the GLP-1 receptors in the nucleus of the solitary tract reduces food reward behavior and targets the mesolimbic system. PLoS One 10 (3), e0119034. doi:10.1371/journal.pone.0119034

PubMed Abstract | CrossRef Full Text | Google Scholar

Rosenstock, J., Frias, J., Jastreboff, A. M., Du, Y., Lou, J., Gurbuz, S., et al. (2023). Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet 402 (10401), 529–544. doi:10.1016/S0140-6736(23)01053-X

PubMed Abstract | CrossRef Full Text | Google Scholar

Sachs, S., Bastidas-Ponce, A., Tritschler, S., Bakhti, M., Bottcher, A., Sanchez-Garrido, M. A., et al. (2020). Targeted pharmacological therapy restores beta-cell function for diabetes remission. Nat. Metab. 2 (2), 192–209. doi:10.1038/s42255-020-0171-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Sanchez-Garrido, M. A., Serrano-Lopez, V., Ruiz-Pino, F., Vazquez, M. J., Rodriguez-Martin, A., Torres, E., et al. (2024). Superior metabolic improvement of polycystic ovary syndrome traits after GLP1-based multi-agonist therapy. Nat. Commun. 15 (1), 8498. doi:10.1038/s41467-024-52898-y

PubMed Abstract | CrossRef Full Text | Google Scholar

Schulingkamp, R. J., Pagano, T. C., Hung, D., and Raffa, R. B. (2000). Insulin receptors and insulin action in the brain: review and clinical implications. Neurosci. Biobehav Rev. 24 (8), 855–872. doi:10.1016/s0149-7634(00)00040-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Schwenk, R. W., Baumeier, C., Finan, B., Kluth, O., Brauer, C., Joost, H. G., et al. (2015). GLP-1-oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New Zealand obese (NZO) mice. Diabetologia 58 (3), 604–614. doi:10.1007/s00125-014-3478-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Shi, J., Sabbagh, M. N., and Vellas, B. (2020). Alzheimer's disease beyond amyloid: strategies for future therapeutic interventions. BMJ 371, m3684. doi:10.1136/bmj.m3684

PubMed Abstract | CrossRef Full Text | Google Scholar

Shimano, H., and Sato, R. (2017). SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology. Nat. Rev. Endocrinol. 13 (12), 710–730. doi:10.1038/nrendo.2017.91

PubMed Abstract | CrossRef Full Text | Google Scholar

Shirazi, R. H., Dickson, S. L., and Skibicka, K. P. (2013). Gut peptide GLP-1 and its analogue, Exendin-4, decrease alcohol intake and reward. PLoS One 8 (4), e61965. doi:10.1371/journal.pone.0061965

PubMed Abstract | CrossRef Full Text | Google Scholar

Silva, D. F., Esteves, A. R., Oliveira, C. R., and Cardoso, S. M. (2017). Mitochondrial metabolism power SIRT2-dependent deficient traffic causing alzheimer's-disease related pathology. Mol. Neurobiol. 54 (6), 4021–4040. doi:10.1007/s12035-016-9951-x

PubMed Abstract | CrossRef Full Text | Google Scholar

Stirone, C., Boroujerdi, A., Duckles, S. P., and Krause, D. N. (2005). Estrogen receptor activation of phosphoinositide-3 kinase, akt, and nitric oxide signaling in cerebral blood vessels: rapid and long-term effects. Mol. Pharmacol. 67 (1), 105–113. doi:10.1124/mol.104.004465

PubMed Abstract | CrossRef Full Text | Google Scholar

Stoccoro, A., Siciliano, G., Migliore, L., and Coppede, F. (2017). Decreased methylation of the mitochondrial D-loop region in late-onset alzheimer's disease. J. Alzheimers Dis. 59 (2), 559–564. doi:10.3233/JAD-170139

PubMed Abstract | CrossRef Full Text | Google Scholar

Stojakovic, A., Trushin, S., Sheu, A., Khalili, L., Chang, S. Y., Li, X., et al. (2021). Partial inhibition of mitochondrial complex I ameliorates Alzheimer's disease pathology and cognition in APP/PS1 female mice. Commun. Biol. 4 (1), 61. doi:10.1038/s42003-020-01584-y

PubMed Abstract | CrossRef Full Text | Google Scholar

Suzuki, S., Brown, C. M., and Wise, P. M. (2006). Mechanisms of neuroprotection by estrogen. Endocrine 29 (2), 209–215. doi:10.1385/ENDO:29:2:209

PubMed Abstract | CrossRef Full Text | Google Scholar

Tatar, M., Bartke, A., and Antebi, A. (2003). The endocrine regulation of aging by insulin-like signals. Science 299 (5611), 1346–1351. doi:10.1126/science.1081447

PubMed Abstract | CrossRef Full Text | Google Scholar

Terao, I., and Kodama, W. (2024). Comparative efficacy, tolerability, and acceptability of donanemab, lecanemab, aducanumab, melatonin, and aerobic exercise for a short time on cognitive function in mild cognitive impairment and mild Alzheimer's disease: a systematic review and network meta-analysis. J. Alzheimers Dis. 98 (3), 825–835. doi:10.3233/JAD-230911

PubMed Abstract | CrossRef Full Text | Google Scholar

Tian, X., Gao, Y., Kong, M., Zhao, L., Xing, E., Sun, Q., et al. (2023). GLP-1 receptor agonist protects palmitate-induced insulin resistance in skeletal muscle cells by up-regulating sestrin2 to promote autophagy. Sci. Rep. 13 (1), 9446. doi:10.1038/s41598-023-36602-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Tian, Z., Fan, J., Zhao, Y., Bi, S., Si, L., and Liu, Q. (2013). Estrogen receptor beta treats Alzheimer's disease. Neural Regen. Res. 8 (5), 420–426. doi:10.3969/j.issn.1673-5374.2013.05.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Tiano, J. P., Tate, C. R., Yang, B. S., DiMarchi, R., and Mauvais-Jarvis, F. (2015). Effect of targeted estrogen delivery using glucagon-like peptide-1 on insulin secretion, insulin sensitivity and glucose homeostasis. Sci. Rep. 5, 10211. doi:10.1038/srep10211

PubMed Abstract | CrossRef Full Text | Google Scholar

Turton, M. D., O'Shea, D., Gunn, I., Beak, S. A., Edwards, C. M., Meeran, K., et al. (1996). A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379 (6560), 69–72. doi:10.1038/379069a0

PubMed Abstract | CrossRef Full Text | Google Scholar

Ulhaq, Z. S., and Garcia, C. P. (2021). Estrogen receptor beta (ESR2) gene polymorphism and susceptibility to dementia. Acta Neurol. Belg 121 (5), 1281–1293. doi:10.1007/s13760-020-01360-z

PubMed Abstract | CrossRef Full Text | Google Scholar

Valdes-Sustaita, B., Estrada-Camarena, E., Gonzalez-Trujano, M. E., and Lopez-Rubalcava, C. (2021). Estrogen receptors-beta and serotonin mediate the antidepressant-like effect of an aqueous extract of pomegranate in ovariectomized rats. Neurochem. Int. 142, 104904. doi:10.1016/j.neuint.2020.104904

PubMed Abstract | CrossRef Full Text | Google Scholar

van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., et al. (2023). Lecanemab in early Alzheimer's disease. N. Engl. J. Med. 388 (1), 9–21. doi:10.1056/NEJMoa2212948

PubMed Abstract | CrossRef Full Text | Google Scholar

Vargas, K. G., Milic, J., Zaciragic, A., Wen, K. X., Jaspers, L., Nano, J., et al. (2016). The functions of estrogen receptor beta in the female brain: a systematic review. Maturitas 93, 41–57. doi:10.1016/j.maturitas.2016.05.014

PubMed Abstract | CrossRef Full Text | Google Scholar

Veliskova, J., and Desantis, K. A. (2013). Sex and hormonal influences on seizures and epilepsy. Horm. Behav. 63 (2), 267–277. doi:10.1016/j.yhbeh.2012.03.018

PubMed Abstract | CrossRef Full Text | Google Scholar

Vogel, H., Wolf, S., Rabasa, C., Rodriguez-Pacheco, F., Babaei, C. S., Stober, F., et al. (2016). GLP-1 and estrogen conjugate acts in the supramammillary nucleus to reduce food-reward and body weight. Neuropharmacology 110 (Pt A), 396–406. doi:10.1016/j.neuropharm.2016.07.039

PubMed Abstract | CrossRef Full Text | Google Scholar

Volgman, A. S., Koschinsky, M. L., Mehta, A., and Rosenson, R. S. (2024). Genetics and pathophysiological mechanisms of lipoprotein(a)-associated cardiovascular risk. J. Am. Heart Assoc. 13 (12), e033654. doi:10.1161/JAHA.123.033654

PubMed Abstract | CrossRef Full Text | Google Scholar

Walsh, S., Merrick, R., Milne, R., and Brayne, C. (2021). Aducanumab for Alzheimer's disease? BMJ 374, n1682. doi:10.1136/bmj.n1682

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, J., Xiong, S., Xie, C., Markesbery, W. R., and Lovell, M. A. (2005). Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer's disease. J. Neurochem. 93 (4), 953–962. doi:10.1111/j.1471-4159.2005.03053.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Warner, M., and Gustafsson, J. A. (2015). Estrogen receptor β and Liver X receptor β: biology and therapeutic potential in CNS diseases. Mol. Psychiatry 20 (1), 18–22. doi:10.1038/mp.2014.23

PubMed Abstract | CrossRef Full Text | Google Scholar

Weidling, I. W., Wilkins, H. M., Koppel, S. J., Hutfles, L., Wang, X., Kalani, A., et al. (2020). Mitochondrial DNA manipulations affect tau oligomerization. J. Alzheimers Dis. 77 (1), 149–163. doi:10.3233/JAD-200286

PubMed Abstract | CrossRef Full Text | Google Scholar

Weiser, M. J., Foradori, C. D., and Handa, R. J. (2008). Estrogen receptor beta in the brain: from form to function. Brain Res. Rev. 57 (2), 309–320. doi:10.1016/j.brainresrev.2007.05.013

PubMed Abstract | CrossRef Full Text | Google Scholar

Yaribeygi, H., Rashidy-Pour, A., Atkin, S. L., Jamialahmadi, T., and Sahebkar, A. (2021). GLP-1 mimetics and cognition. Life Sci. 264, 118645. doi:10.1016/j.lfs.2020.118645

PubMed Abstract | CrossRef Full Text | Google Scholar

Yin, F. (2023). Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise. FEBS J. 290 (6), 1420–1453. doi:10.1111/febs.16344

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, X., Zhou, K., Wang, R., Cui, J., Lipton, S. A., Liao, F. F., et al. (2007). Hypoxia-inducible factor 1alpha (HIF-1alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation. J. Biol. Chem. 282 (15), 10873–10880. doi:10.1074/jbc.M608856200

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhao, Z., Sagare, A. P., Ma, Q., Halliday, M. R., Kong, P., Kisler, K., et al. (2015). Central role for PICALM in amyloid-beta blood-brain barrier transcytosis and clearance. Nat. Neurosci. 18 (7), 978–987. doi:10.1038/nn.4025

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: Alzheimerr′s disease, GLP-1 agonists, estrogens, prevention, metabolism

Citation: Lizcano F, Sanabria D and Aviles E (2025) Hormonal modulation, mitochondria and Alzheimer’s prevention: the role of GLP-1 agonists and estrogens. Front. Mol. Biosci. 12:1622186. doi: 10.3389/fmolb.2025.1622186

Received: 02 May 2025; Accepted: 02 June 2025;
Published: 26 June 2025.

Edited by:

Roberta Marongiu, Cornell University, United States

Reviewed by:

Larance Ronsard, Ragon Institute, United States
Jorge Felipe Argenta Model, Federal University of Rio Grande do Sul, Brazil

Copyright © 2025 Lizcano, Sanabria and Aviles. 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: Fernando Lizcano, ZmVybmFuZG9sbEB1bmlzYWJhbmEuZWR1LmNv

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.