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How Glial Cell Dysfunction Fuels Neurodegeneration in Alzheimer’s and Prion Diseases? Emerging Targets for Therapy

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Saima Zafar, Urwah Rasheed and Inga Zerr

Submitted: 09 October 2025 Reviewed: 15 October 2025 Published: 25 February 2026

DOI: 10.5772/intechopen.1013648

Glia Cells and Their Role in Maintenance, Protection, and Development of the Central Nervous System IntechOpen
Glia Cells and Their Role in Maintenance, Protection, and Develop... Edited by María Elena Hernández Aguilar

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Glia Cells and Their Role in Maintenance, Protection, and Development of the Central Nervous System [Working Title]

María Elena Hernández Aguilar, Jorge Manzo and Hugo Manuel Libreros Jiménez

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Abstract

Neurodegenerative diseases, including Alzheimer’s disease (AD) and prion disorders, have historically been studied from a neuron-centric perspective. However, growing evidence highlights glial cells – particularly microglia and astrocytes – as central mediators of disease initiation and progression. Glia maintain central nervous system homeostasis through waste clearance, synaptic regulation, metabolic support, and blood–brain barrier maintenance. In pathological contexts, glial populations undergo morphological and functional changes, commonly termed reactive gliosis, which can be either protective or detrimental depending on the disease stage. In AD, microglial dysfunction impairs amyloid clearance, promotes chronic cytokine release, and contributes to synaptic loss, while reactive astrocytes exacerbate glutamate excitotoxicity and metabolic dysregulation. Similarly, prion diseases demonstrate that glial cells mediate neurotoxicity and pathogen propagation, with astrocytes showing transcriptomic alterations preceding neuronal demise and microglial ablation paradoxically accelerating disease. Shared pathomechanisms between AD and prion diseases include mitochondrial dysfunction, inflammasome activation, cytokine network dysregulation, and impaired phagocytosis, with the NLRP3 inflammasome emerging as a key therapeutic target. Recent advances in single-cell transcriptomics and spatial proteomics are elucidating the molecular heterogeneity of reactive glia, paving the way for precision medicine approaches. Given the challenges of directly targeting misfolded proteins, glia-focused therapies – ranging from anti-inflammatory agents to gene therapy – represent a promising avenue. This chapter reviews the multifaceted roles of glial cells in neurodegeneration, emphasizing how chronic activation, impaired signaling, and genetic susceptibility convert protective functions into drivers of neuronal dysfunction, and explores emerging strategies for glia-targeted interventions in AD and prion diseases.

Keywords

  • glial cells
  • Alzheimer’s disease
  • prion diseases
  • neurodegeneration
  • neuroinflammation
  • reactive gliosis
  • microglia
  • astrocytes
  • therapeutic targets
  • protein misfolding

1. Introduction

Neurodegenerative diseases, including Alzheimer’s disease (AD) and prion diseases, are characterized by progressive neuronal loss, synaptic dysfunction, and the accumulation of misfolded proteins [1]. Traditionally, these disorders have been viewed through a neuron-centric lens. However, growing evidence has repositioned glial cells, particularly astrocytes and microglia, as central players in the pathogenesis and progression of neurodegeneration [2]. Far from being passive bystanders, glial cells actively shape disease environments through inflammatory signaling, failed clearance of pathological proteins, and dysfunctional metabolic support [3, 4].

Glial cells are required for the homeostatic maintenance of the central nervous system (CNS) [5]. The resident immune cell in the brain, the microglia, actively monitors the brain environment, clears waste, and regulates synaptic elimination during development and disease [6]. The most common glial subpopulation, astrocytes, mediate the presence of neurotransmitters, ion equilibrium, energy production, and blood–brain barrier (BBB) health [7]. Oligodendrocytes offer support factors and enable the swift transmission of signals through myelination. In pathological situations, such glial populations experience morphological and functional modifications, usually considered together as the process of gliosis or reactive gliosis, which may be beneficial or harmful depending on the nature of a disease and its temporal progression [8].

Neuroinflammation has been established as a central pathological determinant in AD, and glial cells have found themselves in the limelight in terms of disease progression. The presence of several AD risk genes that are mainly expressed in microglia (TREM2, CD33, and CR1) supports the role of innate immune signaling in susceptibility to the disease, as detected in genome-wide association studies (GWASs) [9]. Dysfunction of microglia causes abnormal clearance of amyloid plaques, over-secretion of cytokines, and loss of synapses. Similarly, astrocytes become reactive and are no longer able to maintain homeostatic activity, a factor that promotes glutamate excitotoxicity and dysregulation of metabolism [10]. The current paradigm shift regarding AD research identifies that glial dysfunction is not only a by-product of the disorder but could also be among the initial and driving causes of neurodegeneration.

Protein misfolding and glial involvement can be better viewed through prion diseases, albeit lesser frequency. Under such conditions, a template-like conformational conversion facilitates the spread of misfolded prion protein (PrP 23), causing massive neurotoxicity. It is remarkable that prion replication and neurodegeneration may develop independently of a substantial adaptive immune response, suggesting that both innate immune cells, in particular microglia and astrocytes, are important mediators of the pathogenesis [11]. The ablation of microglia in mouse models of prion disease has similarly been paradoxically shown to accelerate progression, suggesting a dual role of microglia in neurotoxicity as well as neuroprotection [12]. Astrocytes are another type of cell that contain PrPSc; they also have transcriptomic alterations that precede neuronal demise, hinting at them being the main agents of pathogen propagation and toxicity [13].

One commonality between AD and prion illnesses is the presence of glial phenotypes associated with a patho-mechanistic framework, such as mitochondrial dysfunction, cytokine network dysregulation, inflammasome activation, and impaired phagocytosis. An example is provided by the NLRP3 inflammasome, which has proven that its stimulation in microglia provokes chronic inflammation as well as neuronal damage. NLRP3 and its downstream effectors are therapeutically viable in preclinical models of AD and prion disease [14]. Similarly, it has been demonstrated that manipulating microglial receptors like TREM2 is sufficient to reshape glial reactions and reduce the illness burden [15].

Given the difficulties in directly targeting misfolded proteins, therapeutic approaches that target glial cells present a possible path for intervention. These strategies include repurposing anti-inflammatory drugs, gene therapy, small compounds, and monoclonal antibodies. A major obstacle, though, is the variation in glial responses throughout illness stages and brain areas. The intricate molecular markers of reactive glia are being deciphered through recent developments in single-cell transcriptomics and spatial proteomics, opening the door for precision medicine techniques [16].

This chapter focuses on the multifaceted roles of glial cells in AD and prion diseases (Figure 1). It outlines how their protective functions are undermined by chronic activation, impaired signaling, and genetic susceptibility. Furthermore, it examines how glia contribute to both the propagation of neurotoxicity and the modulation of synaptic integrity, and how this understanding may lead to novel glia-targeted therapeutic strategies.

Figure 1.

The figure depicts how glial cells and inflammatory pathways function differently in neurodegeneration in a healthy brain as opposed to an AD-affected brain (driven by Aβ, tau, and the NLRP3 inflammasome) and a prion disease-affected brain (driven by PrPSc and activated astroglia).

2. Astrocytes in Alzheimer’s disease

The most common glial cells in the CNS are astrocytes, which play a central role in maintaining the CNS by regulating neurotransmitter clearance, ion buffering, brain–blood flow, and metabolism [7]. The star-shaped cells are also crucial in synapse development, elimination, and support [17]. Astrocytes in AD undergo extensive functional and morphological modifications, known as reactive astrocytosis, which is accompanied by an increase in glial fibrillary acidic protein (GFAP) expression, cellular hypertrophy, proliferation, and the release of inflammatory molecules [18].

Although the initial stimulation of astrocyte cells is defensive in nature (intending to regain CNS balance), continuous stimulation causes the loss of supportive roles and the escalation of inflammation, which promotes the development of diseases [19]. Below, we explore the multifaceted role of astrocytes in AD pathogenesis.

2.1 Interaction with amyloid-β

The key underlying pathology of AD is the production of plaques from amyloid-β (Aβ) aggregation. Astrocytes play a dual and time-dependent role in Aβ metabolism, as depicted in Figure 2. In the initial phases, the astrocytes engulf Aβ via the low-density lipoprotein receptor-related protein 1 (LRP1) receptor and degrade it through the lysosomal mechanism, thus reducing the formation of plaques [20, 21]. However, as the disease progresses, the ability of astrocytes to clear Aβ also diminishes. Aβ plaques are surrounded by reactive astrocytes that have taken on a pro-inflammatory appearance and secrete cytokines such as IL-1β, TNF-α, and IL-6 [22]. This inflammatory environment in the nervous tissue increases synaptic dysfunction as well as neuronal damage.

Figure 2.

Astrocyte function in health and diseased brain. Healthy astrocytes clear Aβ to maintain CNS balance, while diseased astrocytes release inflammatory cytokines causing neuronal damage.

Furthermore, astrocytes themselves contain intracellular Aβ, which disrupts the lysosomal activity of the cell and hence worsens the oxidative stress condition [23]. Recently, transcriptomic analyses have been used to describe Aβ-induced astrocytic subpopulations (e.g., disease-associated astrocytes, or DAA), which have dysregulated expression of genes related to CNS inflammation, lipid metabolism, and phagocytosis [24].

2.2 Glutamate dysregulation and excitotoxicity

Astrocytes also play a role in controlling synaptic glutamate homeostasis through the expression of excitatory amino acid transporters, of which EAAT2 (GLT1 in rodents) constitutes more than 90% of brain glutamate uptake [25]. In animal models, impaired EAAT2 clearance and low expression are shown in the brains of humans and animals [26].

This excitotoxicity caused by glutamate leads to calcium overloading, oxidative stress, and finally neuronal apoptosis. Additionally, Aβ oligomers have been shown to impair EAAT2 expression via epigenetic mechanisms and by inducing oxidative modifications on transporter proteins [27]. Hence, therapeutic approaches that may be used to increase the expression or activity of EAAT2 will provide a potential benefit in reducing excitotoxic injury in AD models.

2.3 Astrocytic metabolic failure

Astrocytes normally support neurons through lactate shuttle mechanisms and glycogen metabolism [28]. In AD, astrocytic metabolic function declines, contributing to energy deficits in neurons and reduced resilience to toxic stress [29]. The astrocyte-neuron lactate shuttle refers to a metabolic support provided by astrocytes to neurons, whereby lactate is produced by astrocytes using glucose as a precursor and provided to neurons to generate ATPs [30]. Astrocyte glucose metabolism is impaired in AD, manifesting in the form of low key glycolytic enzyme and glucose transporter (GLUT1 and GLUT3) expression [31].

The failure of this metabolism also contributes to neuronal energy loss, a decrease in synaptic plasticity, and increased susceptibility to Aβ and tau toxicity [32]. The toxic environment is further exacerbated by the impairment of mitochondrial dynamics in astrocytes, characterized by decreased oxidative phosphorylation and elevated production of ROS [33].

2.4 Astrocyte–tau interactions

A central feature of AD is tau pathology, and recent findings indicate an involvement of astrocytes in tau-related neurotoxicity [34]. Despite the role of neurons as the progenitors of pathological tau, astrocytes are capable of incorporating extracellular tau (in particular, its phosphorylated variants) via endocytosis [35]. Nonetheless, instead of completely eliminating it, the astrocytes can also facilitate tau propagation through the secretion of tau-loaded exosomes or even by transferring it to adjacent cells [36].

Besides, tau aggregation causes astrocytes to switch to a reactive phenotype (excessive expression of GFAP and secretion of pro-inflammatory cytokines, e.g., IL-1β, TNF-α), which, in turn, can also destroy neurons [37]. This reciprocal process facilitates the damage of a neuroinflammatory–tau–transmission cycle, which worsens cognitive decline in AD. Research also indicates that astrocytes could alter tau phosphorylation by affecting kinase and phosphatase activity, thereby contributing to the progression of tau pathology in AD [38, 39].

3. Microglia in Alzheimer’s disease

Microglia are the primary innate immune cells of the brain; their progenitors are derived from the yolk sac, and they carry out crucial functions in immune surveillance, clearance of debris, synaptic remodeling, and tissue repair [40]. As illustrated in Figure 3, microglia have been shown to exhibit functional dichotomy in AD: in the early stages, they shift from protective phenotypes to chronic, detrimental activation as the disease progresses [41].

Figure 3.

Microglial dysfunction and neurodegeneration in AD. chronic microglial activation and TREM2 mutations (R47H) reduce Aβ clearance and enhance inflammatory and oxidative stress responses, leading to Aβ and tau accumulation and progressive neurodegeneration.

3.1 Protective roles in early disease

As shown in Figure 3, at the initial phases of AD, microglia are beneficial as they have been observed to recognize Aβ agglomerates via pattern recognition receptors, including Toll-like receptors, CD36, and scavenger receptors [42]. Such recognition induces a protective M2-like reaction, which entails the secretion of anti-inflammatory cytokines such as IL-10 and TGF-β and effective phagocytosis of the Aβ [43]. Another neurotrophic factor released by microglia in this state is brain-derived neurotrophic factor, which promotes neuronal survival and synaptic activity. This period is important in inhibiting Aβ plaque formation and in initiating repair processes, yet it is normally short-lived [44].

3.2 Chronic activation and inflammation

With more severe AD pathology, continuing exposure to Aβ, oxidative damage, and damage-associated molecular patterns switches the microglial phenotype to a pro-inflammatory (M1-like) state [45]. This phenomenon results in the release of IL-1β, IL-6, TNF-α, the formation of reactive oxygen species (ROS) and nitric oxide (NO) in a neurotoxic environment, which decreases the ability of the microglia to phagocytize Aβ and degenerate cells, and increases the synaptic lesion and the death of neurons [46]. Moreover, this inflammatory signaling could also lead to hyperphosphorylation and spreading of tau, which further contributes to the progression of cognitive decline [47].

3.3 TREM2 and genetic susceptibility

The microglial surface receptor known as TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is essential for phagocytosis, Aβ binding, lipid sensing, and energy metabolism regulation [144]. TREM2 variations, especially the R47H mutation, have been found to be important genetic risk factors for late-onset AD by GWASs [48]. Signaling through TREM2 is key to the activation of a microglial subtype referred to as disease-associated microglia (DAM), the activation of which is marked by the up regulation of phagocytic and lipid metabolism genes [49]. In the AD models, loss of TREM2 causes the microglia to fail in clustering around Aβ deposition spots, phagocytosis, cholesterol homeostasis, as well as the inability to mark the DAM phenotype [50]. Furthermore, TREM2 induces microglia metabolic reprogramming, causing a shift toward glycolysis over oxidative phosphorylation, needed to provide the energetic aspect of phagocytosis and inflammatory responses [51]. The alteration of TREM2 signaling pathway consequently impairs the plasticity of microglia in the AD brain and promotes unrestricted neurodegeneration [52].

3.4 Synaptic pruning deficits

During brain development, microglia are critical in the process of synaptic pruning and in maintaining synaptic plasticity in adulthood. This is achieved through the classical complement cascade, especially the proteins C1q and C3, which mark synapses to be removed [53]. The complement, consisting of the complement receptor 3 (CR3), targets the C3-labeled synapses and causes their degradation following engulfment by the microglial cells [54].

This process of pruning is deregulated in AD. In AD mouse models, it was found that the new addition of complement oligomers enhances the expression of complement proteins and synaptic tagging, causing excessive pruning of functional synapses, specifically in the hippocampus and cortex – areas vital for memory and cognition [55]. Activation of complement is highly correlated with the diminishing of early synapses and cognition [56].

Notably, both genetic and pharmacological stimulation of complement activation abrogation in preclinical models of AD has been demonstrated to limit the loss of synapses and enhance behavior [55].

4. Oligodendrocytes and myelin dysfunction in Alzheimer’s disease

Myelin dysfunction and oligodendrocytes have been found to play a significant and, in many cases, underestimated role in the pathogenesis of AD, as depicted in Figure 4 [57]. The oligodendrocytes produce and preserve the myelin sheath, which insulates axons and enables fast transmission of nerve impulses in the CNS [58]. In AD, neuroimaging and postmortem data from multiple studies demonstrated early white matter defects, such as demyelination, thinning of myelin, and disconnection of axons, especially those related to cognitive functioning [59].

Figure 4.

Oligodendrocyte dysfunction. Normally, oligodendrocyte precursor cells (OPCs) turn into mature oligodendrocytes, which help keep myelination healthy. In some disorders, inflammation and microglial activation, which are driven by CD8⁺ T cells, interfere with OPC differentiation, resulting in excessive proliferation of OPCs and demyelination with worsening neuroinflammation.

These early morphological alterations often precede atrophy of gray matter and clinical manifestations, pointing to the fact that oligodendrocyte dysfunction is not a late sequel of neuronal loss but an early and proactive element of disease pathophysiology [60]. In particular, oligodendrocytes are sensitive to oxidative stress and Aβ toxicity, both of which are extensive in AD pathology [61]. Demolition of myelin worsens the action of the axons and the synchronization among neurons, and that translates directly into cognitive deterioration [62]. The results indicate the necessity to change the focus of therapy to the preservation of the functions of, and implementation of, remyelination in order to slow or prevent the development of the disease.

4.1 Oxidative stress

It damages oligodendrocytes, making them vulnerable to Aβ toxicity [63]. Oligodendrocytes survive well in mild oxidative stress, but in severe oxidative stress, they exhibit high susceptibility because of high metabolic requirements and low antioxidative defense compared to other glial cells [64]. Heightened oxidative stress caused by mitochondrial dysfunction, neuroinflammation, and aggregation of Aβ in AD may lead to oligodendrocyte damage. ROS do not only harm oligodendrocyte membranes and mitochondria but also affect their performance in preserving and creating myelin sheaths [65].

In addition, oligodendrocytes are especially susceptible to amyloid-beta toxicity. It has been reported that Aβ peptides interfere with the calcium balance inside the cells, stimulate the oxidation of lipids, and induce apoptotic mechanisms in oligodendrocytes [65]. This impairs their capability to support axons, with consequent impaired white matter integrity. According to postmortem investigations, oligodendrocytes next to Aβ plaques exhibit DNA breakage and oxidative changes, suggesting their susceptibility in the AD brain [66].

4.2 Myelin breakdown

It disrupts axonal conduction and neuronal communication. These myelin sheaths play a major role in the conduction of electrical impulses along the axons. Myelin degradation in AD causes decreased conduction velocity, signal dispersion, and an inability to achieve synchronization of neurons, which is essential in memory and cognition [67]. Diffusion tensor imaging and magnetization transfer imaging studies have indicated white matter degeneration in the early stages of the disease in patients with mild cognitive impairment (MCI) and early AD, which, in some patients, occurs even before hippocampal atrophy [59].

Bartzokis (2011) put forward the myelin model of AD, that is, that the known age-dependent deterioration of myelin brings about a cascade of pathological events, including Aβ deposition and tau over-phosphorylation [66]. These regions that experience the greatest susceptibility to myelin breakdown (e.g., frontal lobes, corpus callosum) coincide with the first parts of the brain to experience cognitive impairments in AD [68]. This helps to explain that the integrity of myelin is more than a marker of the neurodegenerative changes in the disease, but also a driver. Moreover, the disintegration of myelin can be followed by the release of iron and other neurotoxins, contributing even further to the occurrence of oxidative stress and inflammation in the brain [68]. It has also been found that the loss of trophic-supporting oligodendrocytes increases the susceptibility of neurons toward degeneration [69].

4.3 OPC differentiation

Failure limits repair, leading to progressive cognitive impairment. The adult brain contains large numbers of OPCs that produce new oligodendrocytes throughout life, particularly during or after injury or demyelination. However, in AD, the differentiation of OPCs into mature myelinating oligodendrocytes is substantially impaired [70]. It has been found that Aβ oligomers and inflammatory cytokines like TNF-α and IL-1β reduce OPC proliferation and differentiation [71]. This causes impaired remyelination capacity, which complements the progressive loss of white matter integrity. Moreover, Wnt/beta-catenin and Notch signaling pathways, critical to OPC formation, have been dysregulated in AD models due to internal molecular barriers to repair [72]. The inability of OPCs to differentiate restricts endogenous repair and leads to chronic myelin deficits. Such an absence of remyelination not only derails axonal functioning but also negatively affects cognitive activities, including learning, attention, and memory [73].

5. Glial cells in prion diseases

Prion diseases are a group of transmissible and fatal neurodegenerative diseases marked by the misfolding of prion proteins (PrPSc) that spread by converting the regular cellular prion protein (PrPSc) into their diseased form [74]. This distinct self-perpetuating process causes the death of neurons, spongiform degeneration, as well as a rapid loss of cognitive and motor capabilities [75]. Glial cells, especially astrocytes, microglia, and oligodendrocytes, play a significant role in the progression and neuropathology of prion diseases, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and kuru [13]. These cells, traditionally thought of as secondary responders, are now known to play an active role in prion replication, neuroinflammation, and neurodegeneration.

5.1 Astrocytes: Prion carriers and amplifiers

The most prevalent glial cells in the CNS, astrocytes, become highly reactive during the course of prion disease [76]. This increased responsiveness is known as astrogliosis and is accompanied by hypertrophy, elevated GFAP, and altered expression patterns of genes [77]. Although originally considered to be neuroprotective, reactive astrocytes may switch to a maladaptive phenotype that promotes neuroinflammation and neuronal loss [78].

It is worth noting that astrocytes are not simply passive observers to the progress of prion diseases; in fact, they are capable of intracellular replication of prions. In vitro and in vivo experiments showed that even without the involvement of cells of the nervous system, astrocytes can enhance the accumulation and spread of PrPSc [79]. This shows that astrocytes might be prion reservoirs that mediate local amplification as well as intercellular transmission of PrPSc. This activity of the astrocytes infected with prions results in inflammatory cytokines (IL-1, TNF-alpha, and IL-6), which may interfere with synaptic activity, leading to neurotoxicity [80].

Alongside retaining PrPSc, reactive astrocytes secrete a variety of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), TNF-α, and IL-6, which may contribute to neurodegeneration by increasing neuronal stress and disrupting synaptic function [81]. Their protective functions, involving regulation of extracellular ions, clearing neurotransmitters, and providing metabolic support, are diminished too. This further leads to the continued degradation of the CNS microenvironment [82].

5.2 Microglia: Hyperactivation and ineffective clearance

The most familiar CNS immune cells are the microglia, and they form the initial line of defense after prion infection [83]. Activation of the microglia occurs when they detect PrPSc deposition, elicited by morphological alterations, proliferation, and immune activation through the upregulation of immune markers, that is, CD68, MHC-II, and TREM2 [84].

5.2.1 Prolonged inflammation

Prolonged inflammation leads to a cytokine cascade that worsens neuronal loss [85]. Microglial activation is protective at the early stage, as it attempts to phagocytose prion-infected debris and ensure homeostasis; however, in chronic prion disease, this becomes maladaptive [86]. Microglia release prolonged expression of pro-inflammatory mediators, such as TNF-α, IL-1β, and interferon-gamma (IFN-γ), triggering a cytokine storm that disrupts neuron-glia homeostasis and accelerates neurodegeneration [87].

5.2.2 Inefficient phagocytosis

Despite microglial activation, they exhibit limited capacity to clear PrPSc, resisting lysosomal degradation, which results in the accumulation of this misfolded prion protein within microglial cells, which, in turn, contributes to their functional impairment [88]. Microglial activation in the presence of PrPSc leads to the release of ROS and nitric oxide (NO), which are ineffective against the pathogenic protein but contribute to oxidative injury of surrounding neural cells, thereby exacerbating the spongiform degeneration hallmarking prion pathology [89].

This unproductive clearance and persistent oxidative stress generate a negative feedback loop where microglial activation continues, increases neuron injury, and leads to the driven spread of prion diseases [90].

5.2.3 ROS and NO release

Activated microglia secrete ROS and nitric oxide (NO), which are toxic when excessive [91]. These produced molecules damage neuronal membranes, interfere with the functioning of mitochondria, and also increase lipid peroxidation, leading to the characteristic features of vacuolation and spongiform alterations in prion-affected brains [92]. Preventing microglial activation or minimizing the presence of oxidative stress has demonstrated a slowing of disease progression in experimental models, where excessive microglial activation is destructive [93].

5.3 Oligodendrocyte involvement

Oligodendrocytes, the myelinating glial cells of the CNS, play a vital role in axonal integrity, signal conduction, and cellular metabolism [94]. Their contribution to prion diseases is less well-defined than that of astrocytes and microglia, but indirect evidence suggests they are markedly affected [95]. Although the outright direct infection of oligodendrocytes by prions has not been clearly demonstrated, the inflammatory and oxidative conditions of prion disorders are most likely affecting the performance and survival of oligodendrocytes [96]. TNF-alpha and IFN-gamma cytokines are cytotoxic to OPCs, impede their maturation, and restrict their ability to engage in remyelination [97].

6. Therapeutic strategies targeting glial dysfunction

In recent years, it has become clear that glial dysfunction plays an important role in the onset and development of neurodegenerative disorders such as AD and prion disease [98]. There is a considerable shift toward focusing on glial activity modulation in therapy, as an increasing amount of evidence has attributed the role of glial cells, especially astrocytes and microglia, in driving the course of the disease. Disruption of glial cells plays a major role in chronic neuroinflammation, oxidative stress, and neuroglia injury. Therefore, targeting glial cells is a very attractive tactic to stop or reverse neurodegeneration [99].

6.1 Anti-inflammatory agents

Neurodegenerative disorders are characterized by chronic neuroinflammation, which is facilitated by activated glial cells. Regulation of such an inflammatory response through the injection of pharmacological agents may provide a possible avenue to reduce neuronal damage and enhance clinical outcomes [100].

6.1.1 NSAIDs and IL-1β antagonists

The most studied compounds in modulating glial inflammation include non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, and indomethacin. These medicines mainly restrain cyclooxygenase (COX)-1 and COX-2 enzymes, which synthesize prostaglandins – important agents of inflammation. COX-2 in the CNS is upregulated in activated microglia and leads to neurodegenerative cascades by increasing oxidative stress and excitotoxicity [101].

Transgenic mouse models of AD have been used in preclinical trials, proving that chronic treatment with NSAIDs inhibits microglial activation, plaque load, and neuronal loss [102]. It was shown, in particular, that ibuprofen decreased the expression of IL-1beta and TNF-alpha and enhanced cognitive performance in the animal models of AD [55, 103]. The human experiments, however, are contradicted in terms of the clinical trials conducted so far. The ADAPT trial (Alzheimer Disease Anti-inflammatory Prevention Trial) has not demonstrated any protective role of naproxen or celecoxib against dementia among patients with MCIs, and some NSAIDs have been reported to have cardiovascular risks [104]. This has diverted the focus to more specific cytokine inhibitory strategies, that is, IL-1 block antagonists.

Activated microglia produce an extremely strong pro-inflammatory cytokine, IL-1β [105]. It enhances the activation of astrocytes, impairs synaptic plasticity, and increases the neuroinflammatory loop. Clinical use of Anakinra, a recombinant IL-1 receptor antagonist (IL-1 Ra), has been observed in autoimmune diseases such as rheumatoid arthritis. In neurodegenerative models, the administration of IL-1 Ra suppressed the activation of glial cells, the accumulation of amyloid, and the phosphorylation of tau [106].

Furthermore, higher concentrations of IL-1 in the cerebrospinal fluid (CSF) have been linked to both the course of AD and the prion diseases, further demonstrating its therapeutic potential as a target [107, 108].

6.2 Microglia-targeted therapies

Microglia are the innate immune units of the CNS, which have a dual role in neurodegenerative diseases [109]. In homeostatic states, they mediate synaptic pruning, clearance, and neurotrophic support. However, when chronic microglial activation is present in pathologies such as AD and prion disorders, neuroinflammation, synaptic dysfunction, and neuronal loss occur [110]. Microglia have since then become a significant target in therapy. The two key pathways that are being investigated are TREM2 signaling (as it promotes positive microglial activities) and CSF1R (as it limits excessive or pathological proliferation of microglia) [9].

6.2.1 TREM2 agonists to enhance phagocytosis

Microglia have a particular receptor called triggering receptor expressed on myeloid cells 2 (TREM2) that controls phagocytosis, lipid metabolism, and inflammatory response. Mutations causing loss of function in the TREM2 gene show the protective effect of this gene and predispose people to AD [111, 112]. TREM2 mediates the switch of microglia into a phenotype of their newly understood form, the so-called disease-associated-microglia (DAM), which intensively phagocytose Aβ and apoptotic debris [113].

The treatment interventions (based on TREM2 agonist antibodies) are intended to enhance the effectiveness of microglia. The most prominent example is a monoclonal antibody, AL002 developed by Alector and licensed to AbbVie. Preclinical research demonstrated that AL002 improved TREM2 signaling, amplified microglial aggregation at plaques, lowered amyloid pathology, and maintained synaptic integrity [114].

6.2.2 CSF1R inhibitors to modulate microglial proliferation

Colony-stimulating factor 1 receptor (CSF1R) is a tyrosine kinase receptor important for the survival, proliferation, and differentiation of microglia [115]. Persistent activation or overexpression of CSF1R is associated with neurotoxicity, hyper-microgliosis, and transmission of neurodegeneration, which is linked to the pathology [116, 117].

CSF1R inhibition causes depletion or proliferation arrest in microglia, resulting in decreased neuroinflammation and secondary damage [118]. In mice carrying AD, treatment with a CSF1R inhibitor leads to decreased microgliosis related to plaque parenchyma, reduced cytokines of immune response, and neural protection and functional neurorestoration [119].

While reduction at later stages produced less benefit and ran the risk of compromising synaptic support, a study showed that early and persistent microglial ablation with a CSF1R inhibitor in 5xFAD Alzheimer’s mice decreased amyloid plaque growth, neuronal loss, and enhanced memory [120]. In this way, partial or temporary inhibition is now considered a moderate therapy. The same effects have been observed in prion diseases with inhibition of CSF1R, where elimination of microglia slowed the progression of the disease, decreased levels of PrPSc, and reduced neuronal vacuolation [121]. This supports the hypothesis that proliferative pathogenic microglia contribute to neurodegeneration outside amyloid pathology-based diseases.

6.3 Astrocyte modulators

Astrocytes are key factors in preserving CNS homeostasis by regulating neurotransmitter diffusion, providing support to the BBB, and adjusting synaptic dynamics [89]. However, reactive astrogliosis of the astrocytes is a transformation that occurs during neurodegeneration, characterized by morphological distortion, expression of inflammatory genes, and the loss of homeostatic mechanisms [45]. Treatments that either rejuvenate astrocytes or inhibit pathological reactivity are emerging as potential therapies for AD and prion diseases.

6.3.1 Compounds that upregulate EAAT2 expression

Excitatory amino acid transporter 2 (EAAT2), or more commonly GLT-1 in rodents, removes more than 90% of extracellular glutamate in the CNS and thus eliminates excitatory toxicity – a major causative component of neurodegeneration in various conditions such as AD or amyotrophic lateral sclerosis (ALS). EAAT2 is mostly astroglial, and its reduction is usually reported in neurodegenerative pathologies [122].

The EAAT2-upregulating therapies can work in terms of affecting a restoration of glutamate homeostasis and the prevention of cell death. Among its compounds is the following notable compound:

6.3.1.1 Ceftriaxone

It is a β-lactam antibiotic with a high effect on EAAT2 transcription. Ceftriaxone also increased EAAT2 in vivo and in vitro models, thereby enhancing motor performance and survival in ALS mice. Ceftriaxone therapy in AD models attenuated amyloid pathology and enhanced cognition [122, 123].

6.3.1.2 MS-153 and LDN/OSU-0212320

These are small molecules that are known to stimulate EAAT2 promoter, resulting in either the upregulation of EAAT2 and the removal of neurodegenerative glutamate toxicity in experimental models [124, 125].

In animal models, adeno-associated viral vectors-based gene therapy strategies to express EAAT2 by overexpression appear promising and have been shown to ameliorate neurodegeneration and inflammation [126].

6.3.2 Targeting JAK/STAT signaling in reactive astrogliosis

A significant pathway of the signaling cascade that is associated with reactive astrogliosis is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway [127]. Neurodegenerative diseases are accompanied by long-term activation of the JAK/STAT3 signaling pathway in astrocytes, with a loss of favorable neuroprotective properties and a shift to more neurotoxic behavior [128]. Therefore, the inhibition of maladaptive astrogliosis through JAK/STAT signaling suppression is under development.

6.3.2.1 STAT3 conditional knockout

Conditional knockout of STAT3 in AD mouse models with astrocyte-specific deletion leads to a reduction in astrocyte reactivity and better survival of neurons, along with a smaller number of plaques [129].

6.3.2.2 WP1066 and AG490

These are small molecular inhibitors of JAK2/STAT3 signaling, and with them, astrogliosis and production of cytokines are decreased, resulting in neuroprotection in models of prion disease and traumatic brain injury [130, 131].

Ciliary neurotrophic factor (CNTF): Although CNTF can stimulate the JAK/STAT signaling pathway, low doses or transient activation could reprogram astrocytes toward a pro-protective phenotype, and thus moderate, rather than complete, inhibition of this pathway may be desirable at certain stages of disease progression [128].

6.4 Gene and cell-based therapies

The use of genes and cells is gaining traction in the management of neurodegenerative diseases, particularly those that are glia-prominent, especially AD and prion diseases [132]. The strategies aim to reverse genetic risk factors or remove dysfunctional glia by replacing them with new, healthy, functional cells, which may ultimately stop or even roll back the disease process [133].

6.4.1 CRISPR-Cas9 correction of glial risk alleles (e.g., TREM2, APOE4)

Genetic variants in glia-expressed genes, that is, APOE and TREM2, are found to be predominantly linked with increased chances of AD and neurodegenerative disorders [134]. CRISPR-Cas9 genome editing has made it possible to target such risk alleles at their source and accomplish this in a cell-type-specific fashion.

6.4.1.1 Correction of APOE4

The strongest risk factor in genetic terms for sporadic AD was found to be the APOE4 allele, which is expressed mainly in astrocytes and, more weakly, in microglia. APOE4 promotes poor clearance of Aβ, enhances inflammation, and compounds damage to the BBB. Conversion of APOE4-associated AD patient iPSC-derived astrocytes to an APOE3 isoform with a neutral phenotype using CRISPR-Cas9 regulated cholesterol metabolism, decreased the secretion of Aβ, and enhanced the supporting features of astrocytes [135]. Base editing technologies have demonstrated the possibility of APOE4 to APOE3 in mouse brains both in vitro and in vivo, which decreases neuroinflammation and Aβ load [136].

6.4.1.2 The correction of TREM2

TREM2 is a receptor expressed in microglial cells that mediates phagocytosis and inflammatory responses, and pathogenic forms of TREM2 favor AD by dysregulating microglial responses to Aβ. In a 2021 study, the R47H mutation in microglia derived from induced pluripotent stem cells (iPSCs) was corrected with the help of CRISPR-Cas9. In chimeric mouse models and in vitro, gene-corrected microglia exhibited restored phagocytic ability, a correct metabolic profile, and a better response to plaques [137, 138]

6.4.2 Transplantation of healthy glial progenitors or stem-cell-derived astrocytes

The next potentially promising direction in the transplantation of healthy glial progenitors or astrocytes produced by pluripotent stem cells is glial-targeted therapy [139]. This is aimed at replacing dysfunctional glia and re-establishing the neuroprotective effects of the diseased CNS.

6.4.2.1 Astrocyte transplantation

Transplantation of human embryonic stem-cell-derived astrocytes (hESCs) or induced pluripotent stem-cell-derived astrocytes (iPSCs) into AD and ALS mouse models is possible. This population of astrocytes is characterized by infiltration into the host tissue, stabilization of neurons, absorption of the extracellular form of glutamate, as well as dampening of inflammation [140]. Transplantation of iPSC-derived astrocytes decreased Aβ burden, ameliorated synaptic plasticity, and corrected cognitive impairment in an AD model mouse [141].

6.4.2.2 Transplantation of glial progenitor

Glial progenitor cells (GPCs), which have the potential to differentiate into both astrocytes and oligodendrocytes, are another prospective cellular therapy. GPCs remyelinate axons, enhance behavioral therapies, reduce neuroinflammation, and improve outcomes in leukodystrophy and demyelination in mouse models [142, 143]. Although research on prion diseases is scarce, due to the dense astro-glial/oligo-glial participation in the pathogenesis, the possibility of alleviating functional loss by substituting these cells exists.

7. Conclusion

Alzheimer's disease has long been described primarily in terms of neuronal dysfunction and the pathogenic accumulations of amyloid-beta and tau, but it is now generally regarded as a disease involving the complex interplay among all components of the cells in the CNS. These include the glial cells, which play an instrumental role in the onset and progression of neurodegenerative processes, and encompass astrocytes, microglia, and oligodendrocytes. Astrocytes, once thought to be passive support cells, are now recognized as active modulators of neuroinflammation and neurotransmission. Their reactive phenotype in AD not only disrupts glutamate homeostasis and fuel supply but also contributes to amyloid and tau pathology. Similarly, microglia exhibit highly variable functional roles, where their initial protective response to amyloid-beta is overshadowed by long-term pro-inflammatory activation, which causes neuronal damage, loss of synaptic sites due to complement activity, and defective clearance processes, particularly in carriers of hereditary mutations such as TREM2. Meanwhile, oligodendrocytes and their precursors, which are often overlooked, are also significantly affected by AD pathology. Abnormal neural communication arises from oxidative stress, defective OPC differentiation, and the degeneration of myelin, which exacerbates cognitive decline. These white matter changes are becoming increasingly apparent at early stages in imaging tests and can be detected before the onset of classic AD symptoms. In combination, the malfunction of glial cells can amplify the classical symptomatic pathology of AD and, additionally, represents a therapeutically untapped area of interest. Understanding and modulating glial-specific therapies (e.g., enhancing astrocytic clearance, reprogramming or remodeling microglia, and repairing oligodendrocytes) is another promising avenue for disease-modifying innovations. A potential new perspective on the so-called gliocentric pathology in AD prompts a redefinition of therapeutic approaches to account for the complex and essential functions of glial cells in maintaining CNS homeostasis.

Conflict of Interest

The authors declare no conflict of interest.

References

  1. 1. Jellinger KA. Basic mechanisms of neurodegeneration: A critical update. Journal of Cellular and Molecular Medicine. 2010;14(3):457–487. DOI: 10.1111/j.1582-4934.2010.01010.x
  2. 2. Stobart JL, Anderson CM. Multifunctional role of astrocytes as gatekeepers of neuronal energy supply. Frontiers in Cellular Neuroscience. 2013;7:38. DOI: 10.3389/fncel.2013.00038
  3. 3. Kwon HS, Koh SH. Neuroinflammation in neurodegenerative disorders: The roles of microglia and astrocytes. Translational Neurodegeneration. 2020;9:42. DOI: 10.1186/s40035-020-00221-2
  4. 4. Müller L, Di Benedetto S. Neuroimmune crosstalk in chronic neuroinflammation: Microglial interactions and immune modulation. Frontiers in Cellular Neuroscience. 2025;19:1575022
  5. 5. Quan L, Uyeda A, Muramatsu R. Central nervous system regeneration: The roles of glial cells in the potential molecular mechanism underlying remyelination. Inflammation and Regeneration. 2022;42(1):7. DOI: 10.1186/s41232-022-00193-y
  6. 6. Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annual Review of Immunology. 2017;35:441–468. DOI: 10.1146/annurev-immunol-051116-052358
  7. 7. Verkhratsky A, Butt A, Li B, et al. Astrocytes in human central nervous system diseases: A frontier for new therapies. Signal Transduction and Targeted Therapy. 2023;8:396
  8. 8. Escartin C, Galea E, Lakatos A, et al. Reactive astrocyte nomenclature, definitions, and future directions. Nature Neuroscience. 2021;24:312–325
  9. 9. Villegas-Llerena C, Phillips A, Garcia-Reitboeck P, Hardy J, Pocock JM. Microglial genes regulating neuroinflammation in the progression of Alzheimer’s disease. Current Opinion in Neurobiology. 2016;36:74–81. DOI: 10.1016/j.conb.2015.10.004
  10. 10. Liddelow S, Guttenplan K, Clarke L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481–487
  11. 11. Öztürk MM, Emgård J, García-Revilla J, Fernández-Calle R, Yang Y, Deierborg T, Roos TT. The role of microglia in the prion-like transmission of protein aggregates in neurodegeneration. Brain Communications. 2025;7(2):fcaf087. DOI: 10.1093/braincomms/fcaf087
  12. 12. Bradford BM, McGuire LI, Hume DA, Pridans C, Mabbott NA. Microglia deficiency accelerates prion disease but does not enhance prion accumulation in the brain. Glia. 2022;70(11):2169–2187. DOI: 10.1002/glia.24244
  13. 13. Smethurst P, Franklin H, Clarke BE, Sidle K, Patani R. The role of astrocytes in prion-like mechanisms of neurodegeneration. Brain. 2022;145(1):17–26. DOI: 10.1093/brain/awab366
  14. 14. Ising C, Venegas C, Zhang S, et al. NLRP3 inflammasome activation drives tau pathology. Nature. 2019;575:669–673
  15. 15. Condello C, Yuan P, Neuroprotection GJM-M. TREM2, and Alzheimer’s disease: Evidence from optical imaging. Biological Psychiatry. 2018;83(4):377–387. DOI: 10.1016/j.biopsych.2017.10.007
  16. 16. Gao C, Jiang J, Tan Y, et al. Microglia in neurodegenerative diseases: Mechanism and potential therapeutic targets. Signal Transduction and Targeted Therapy. 2023;8:359
  17. 17. Lawal O, Ulloa Severino FP, Eroglu C. The role of astrocyte structural plasticity in regulating neural circuit function and behavior. Glia. 2022;70(8):1467–1483. DOI: 10.1002/glia.24191
  18. 18. Verkhratsky A, Nedergaard M. Physiology of astroglia. Physiological Reviews. 2018;98(1):239–389. DOI: 10.1152/physrev.00042.2016
  19. 19. Liddelow SA, Barres BA. Reactive astrocytes: Production, function, and therapeutic potential. Immunity. 2017;46(6):957–967
  20. 20. Wyss-Coray T, Loike J, Brionne T, et al. Adult mouse astrocytes degrade amyloid-β in vitro and in situ. Nature Medicine. 2003;9:453–457
  21. 21. Ries M, Sastre M. Mechanisms of Aβ clearance and degradation by glial cells. Frontiers in Aging Neuroscience. 2016;8:160
  22. 22. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Kummer MP et al. Neuroinflammation in Alzheimer’s disease. The Lancet Neurology. 2015;14(4):388–405
  23. 23. Azargoonjahromi A. The duality of amyloid-β: Its role in normal and Alzheimer’s disease states. Molecular Brain. 2024;17(1):44. DOI: 10.1186/s13041-024-01118-1
  24. 24. Habib N, McCabe C, Medina S, et al. Disease-associated astrocytes in Alzheimer’s disease and aging. Nature Neuroscience. 2020;23:701–706
  25. 25. Mahmoud S, Gharagozloo M, Simard C, Gris D. Astrocytes maintain glutamate homeostasis in the CNS by controlling the balance between glutamate uptake and release. Cells. 2019;8(2):184. DOI: 10.3390/cells8020184
  26. 26. Takahashi K, Foster JB, Lin CL. Glutamate transporter EAAT2: Regulation, function, and potential as a therapeutic target for neurological and psychiatric disease. Cellular and Molecular Life Sciences. 2015;72(18):3489–3506. DOI: 10.1007/s00018-015-1937-8
  27. 27. Dong XX, Wang Y, ZH Q. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacologica Sinica. 2009;30(4):379–387. DOI: 10.1038/aps.2009.24
  28. 28. Mason S. Lactate shuttles in neuroenergetics—homeostasis, allostasis and beyond. Frontiers in Neuroscience. 2017;11:43
  29. 29. Beard E, Lengacher S, Dias S, Magistretti PJ, Finsterwald C. Astrocytes as key regulators of brain energy metabolism: New therapeutic perspectives. Frontiers in Physiology. 2022;12:825816
  30. 30. Kim Y, Dube SE, Park CB. Brain energy homeostasis: The evolution of the astrocyte-neuron lactate shuttle hypothesis. The Korean Journal of Physiology & Pharmacology. 2025;29(1):1–8. DOI: 10.4196/kjpp.24.388
  31. 31. Raut S, Bhalerao A, Powers M, Gonzalez M, Mancuso S, Cucullo L. Hypometabolism, Alzheimer’s disease, and possible therapeutic targets: An overview. Cells. 2023;12(16):2019. DOI: 10.3390/cells12162019
  32. 32. Yuan Y, Zhao G, Zhao Y. Dysregulation of energy metabolism in Alzheimer’s disease. Journal of Neurology. 2024;272(1):2. DOI: 10.1007/s00415-024-12800-8
  33. 33. Meng K, Jia H, Hou X, Zhu Z, Lu Y, Feng Y, Feng J, Xia Y, Tan R, Cui F, Yuan J. Mitochondrial dysfunction in neurodegenerative diseases: Mechanisms and corresponding therapeutic strategies. Biomedicines. 2025;13(2):327. DOI: 10.3390/biomedicines13020327
  34. 34. Chen Y, Yu Y. Tau and neuroinflammation in Alzheimer’s disease: Interplay mechanisms and clinical translation. Journal of Neuroinflammation. 2023;20:165. DOI: 10.1186/s12974-023-02853-3
  35. 35. Brunello CA, Merezhko M, Uronen RL, Huttunen HJ. Mechanisms of secretion and spreading of pathological tau protein. Cellular and Molecular Life Sciences. 2020;77(9):1721–1744. DOI: 10.1007/s00018-019-03349-1
  36. 36. Deng Q, Wu C, Parker E, Liu TC, Duan R, Yang L. Microglia and astrocytes in Alzheimer’s disease: Significance and summary of recent advances. Aging and Disease. 2024;15(4):1537–1564. DOI: 10.14336/AD.2023.0907
  37. 37. Han J, Zhang Z, Zhang P, Yu Q, Cheng Q, Lu Z, Zong S. The roles of microglia and astrocytes in neuroinflammation of Alzheimer’s disease. Frontiers in Neuroscience. 2025;19:1575453. DOI: 10.3389/fnins.2025.1575453
  38. 38. Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W. Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death & Disease. 2011;2(6):e167. DOI: 10.1038/cddis.2011.50
  39. 39. Bellaver B, Povala G, Ferreira PC, Ferrari-Souza JP, Leffa DT, Lussier FZ, Pascoal TA et al. Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer’s disease. Nature Medicine. 2023;29(7):1775–1781
  40. 40. Casali BT, Reed-Geaghan EG. Microglial function and regulation during development, homeostasis and Alzheimer’s disease. Cells. 2021;10(4):957. DOI: 10.3390/cells10040957
  41. 41. Valiukas Z, Tangalakis K, Apostolopoulos V, Feehan J. Microglial activation states and their implications for Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease. 2025;100013
  42. 42. Jin JJ, Kim HD, Maxwell JA, Li L, Fukuchi KI. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer’s disease. Journal of Neuroinflammation. 2008;5:1–10
  43. 43. Cherry JD, Olschowka JA, O’Banion MK. Neuroinflammation and M2 microglia: The good, the bad, and the inflamed. Journal of Neuroinflammation. 2014;11:98. DOI: 10.1186/1742-2094-11-98
  44. 44. Trang T, Beggs S, Salter MW. Brain-derived neurotrophic factor from microglia: A molecular substrate for neuropathic pain. Neuron Glia Biology. 2011;7(1):99–108. DOI: 10.1017/S1740925X12000087
  45. 45. Ghimire A, Rehman SA, Subhani A, Khan MA, Rahman Z, Iqubal MK, Iqubal A. Mechanism of microglia-mediated neuroinflammation, associated cognitive dysfunction, and therapeutic updates in Alzheimer’s disease. hLife. 2025;3:64–81
  46. 46. Cai Y, Liu J, Wang B, Sun M, Yang H. Microglia in the neuroinflammatory pathogenesis of Alzheimer’s disease and related therapeutic targets. Frontiers in Immunology. 2022;13:856376. DOI: 10.3389/fimmu.2022.856376
  47. 47. Dias D, Socodato R. Beyond amyloid and tau: The critical role of microglia in Alzheimer’s disease therapeutics. Biomedicines. 2025;13(2):279. DOI: 10.3390/biomedicines13020279
  48. 48. Yaghmoor F, Noorsaeed A, Alsaggaf S, Aljohani W, Scholtzova H, Boutajangout A, Wisniewski T. The role of TREM2 in Alzheimer’s disease and other neurological disorders. Journal of Alzheimer’s Disease & Parkinsonism. 2014;4(5):160. DOI: 10.4172/2161-0460.1000160
  49. 49. Cantoni C, Bollman B, Licastro D, Xie M, Mikesell R, Schmidt R, Yuede CM, Galimberti D, Olivecrona G, Klein RS, Cross AH, Otero K, Piccio L. TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathologica. 2015;129(3):429–447. DOI: 10.1007/s00401-015-1388-1
  50. 50. Zhang L, Xiang X, Li Y, Bu G, Chen XF. TREM2 and sTREM2 in Alzheimer’s disease: From mechanisms to therapies. Molecular Neurodegeneration. 2025;20(1):43. DOI: 10.1186/s13024-025-00834-z
  51. 51. Huang Q, Wang Y, Chen S, Liang F. Glycometabolic reprogramming of microglia in neurodegenerative diseases: Insights from neuroinflammation. Aging and Disease. 2024;15(3):1155–1175. DOI: 10.14336/AD.2023.0807
  52. 52. Shi Q, Gutierrez RA, Bhat MA. Microglia, Trem2, and neurodegeneration. The Neuroscientist: A Review Journal Bringing Neurobiology, Neurology and Psychiatry. 2025;31(2):159–176. DOI: 10.1177/10738584241254118
  53. 53. Wu Y, Dissing-Olesen L, MacVicar BA, Stevens B. Microglia: dynamic mediators of synapse development and plasticity. Trends in Immunology. 2015;36(10):605–613. DOI: 10.1016/j.it.2015.08.008
  54. 54. Paolicelli RC, Ferretti MT. Function and dysfunction of microglia during brain development: Consequences for synapses and neural circuits. Frontiers in Synaptic Neuroscience. 2017;9:9. DOI: 10.3389/fnsyn.2017.00009
  55. 55. Shi Q, Chowdhury S, Ma R, Le KX, Hong S, Caldarone BJ, Stevens B, Lemere CA. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Science Translational Medicine. 2017;9(392):eaaf6295. DOI: 10.1126/scitranslmed.aaf6295
  56. 56. Spurrier J, Nicholson L, Fang XT, Stoner AJ, Toyonaga T, Holden D, Siegert TR, Laird W, Allnutt MA, Chiasseu M, Brody AH, Takahashi H, Nies SH, Pérez-Cañamás A, Sadasivam P, Lee S, Li S, Zhang L, Huang YH, Carson RE, Strittmatter SM. Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q. Science Translational Medicine. 2022;14(647):eabi8593. DOI: 10.1126/scitranslmed.abi8593
  57. 57. Badina AM, Ceyzériat K, Amossé Q, Tresh A, Abjean L, Guénat L, Tournier BB, et al. Non-linear microglial, inflammatory and oligodendrocyte dynamics across stages of Alzheimer’s disease. Neurobiology of Disease. 2025;106950
  58. 58. Simons M, Nave KA. Oligodendrocytes: Myelination and axonal support. Cold Spring Harbor Perspectives in Biology. 2015;8(1):a020479. DOI: 10.1101/cshperspect.a020479
  59. 59. Zhou J, Zhang P, Zhang B, Kong Y. White matter damage in Alzheimer’s disease: Contribution of oligodendrocytes. Current Alzheimer Research. 2022;19(9):629–640. DOI: 10.2174/1567205020666221021115321
  60. 60. Nasrabady SE, Rizvi B, Goldman JE, et al. White matter changes in Alzheimer’s disease: A focus on myelin and oligodendrocytes. Acta Neuropathologica Communications. 2018;6(22). DOI: 10.1186/s40478-018-0515-3
  61. 61. Desai MK, Mastrangelo MA, Ryan DA, Sudol KL, Narrow WC, Bowers WJ. Early oligodendrocyte/myelin pathology in Alzheimer’s disease mice constitutes a novel therapeutic target. The American Journal of Pathology. 2010;177(3):1422–1435. DOI: 10.2353/ajpath.2010.100087
  62. 62. Khelfaoui H, Ibaceta-Gonzalez C, Angulo MC. Functional myelin in cognition and neurodevelopmental disorders. Cellular and Molecular Life Sciences. 2024;81(1):181. DOI: 10.1007/s00018-024-05222-2
  63. 63. Roth AD, Ramírez G, Alarcón R, Von Bernhardi R. Oligodendrocytes damage in Alzheimer’s disease: Beta amyloid toxicity and inflammation. Biological Research. 2005;38(4):381–387
  64. 64. Jy K, JH K, Yd K, Seo JH. High vulnerability of oligodendrocytes to oxidative stress induced by ultrafine urban particles. Antioxidants (Basel). 2020;10(1):4. DOI: 10.3390/antiox10010004
  65. 65. Spaas J, van Veggel L, Schepers M, Tiane A, van Horssen J, Wilson 3rd DM, Moya PR, Piccart E, Hellings N, Eijnde BO, Derave W, Schreiber R, Vanmierlo T. Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders. Cellular and Molecular Life Sciences. 2021;78(10):4615–4637. DOI: 10.1007/s00018-021-03802-0
  66. 66. Bartzokis G. Alzheimer’s disease as homeostatic responses to age-related myelin breakdown. Neurobiology of Aging. 2011;32(8):1341–1371
  67. 67. Papuć E, Rejdak K. The role of myelin damage in Alzheimer’s disease pathology. Archives of Medical Science. 2018;16(2):345–351. DOI: 10.5114/aoms.2018.76863
  68. 68. Bartzokis G, Lu PH, Mintz J. Human brain myelination and amyloid beta deposition in Alzheimer’s disease. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. 2007;3(2):122–125. DOI: 10.1016/j.jalz.2007.01.019
  69. 69. Maitre M, Jeltsch-David H, Okechukwu NG, et al. Myelin in Alzheimer’s disease: Culprit or bystander? Acta Neuropathologica Communications. 2023;11(56). DOI: 10.1186/s40478-023-01554-5
  70. 70. El Waly B, Macchi M, Cayre M, Durbec P. Oligodendrogenesis in the normal and pathological central nervous system. Frontiers in Neuroscience. 2014;8:145. DOI: 10.3389/fnins.2014.00145
  71. 71. Beiter RM, Raghavan TP, Suchocki O, Ennerfelt HE, Rivet-Noor CR, Merchak AR, Phillips JL, Bathe T, Lukens JR, Prokop S, Dupree JL, Gaultier A. Oligomeric amyloid beta prevents myelination in a clusterin-dependent manner. Research Square. 2024; DOI: 10.21203/rs.3.rs-4415143/v1. rs.3.rs-4415143
  72. 72. Zou P, Wu C, Liu TC, Duan R, Yang L. Oligodendrocyte progenitor cells in Alzheimer’s disease: From physiology to pathology. Translational Neurodegeneration. 2023;12(1):52. DOI: 10.1186/s40035-023-00385-7
  73. 73. Zveik O, Rechtman A, Ganz T, Vaknin-Dembinsky A. The interplay of inflammation and remyelination: Rethinking MS treatment with a focus on oligodendrocyte progenitor cells. Molecular Neurodegeneration. 2024;19(1):53. DOI: 10.1186/s13024-024-00742-8
  74. 74. Prusiner SB, Prions. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(23):13363–13383. DOI: 10.1073/pnas.95.23.13363
  75. 75. Hughes D, Halliday M. What is our current understanding of PrPSc-associated neurotoxicity and its molecular underpinnings? Pathogens (Basel, Switzerland). 2017;6(4):63. DOI: 10.3390/pathogens6040063
  76. 76. Hay A, Popichak K, Moreno J, Zabel M. The role of glial cells in neurobiology and prion neuropathology. Cells. 2024;13(10):832. DOI: 10.3390/cells13100832
  77. 77. Lawrence JM, Schardien K, Wigdahl B, Nonnemacher MR. Roles of neuropathology-associated reactive astrocytes: A systematic review. Acta Neuropathologica Communications. 2023;11(1):42. DOI: 10.1186/s40478-023-01526-9
  78. 78. Ding ZB, Song LJ, Wang Q, Kumar G, Yan YQ, Ma CG. Astrocytes: A double-edged sword in neurodegenerative diseases. Neural Regeneration Research. 2021;16(9):1702–1710. DOI: 10.4103/1673-5374.306064
  79. 79. Tahir W, Thapa S, Schatzl HM. Astrocyte in prion disease: A double-edged sword. Neural Regeneration Research. 2022;17(8):1659–1665. DOI: 10.4103/1673-5374.332202
  80. 80. Lakkaraju AKK, Sorce S, Senatore A, Nuvolone M, Guo J, Schwarz P, Moos R, Pelczar P, Aguzzi A. Glial activation in prion diseases is selectively triggered by neuronal PrPSc. Brain Pathology (Zurich, Switzerland). 2022;32(5):e13056. DOI: 10.1111/bpa.13056
  81. 81. Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, Tran T, Ubeda O, Ashe KH, Frautschy SA, Cole GM. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. The Journal of Neuroscience. 2000;20(15):5709–5714. DOI: 10.1523/JNEUROSCI.20-15-05709.2000
  82. 82. Assis-de-lemos G, Moura-do-nascimento R, Amaral-do-nascimento M, Miceli AC, Vieira TCRG. Interactions between cytokines and the pathogenesis of prion diseases: Insights and implications. Brain Sciences. 2024;14(5):413. DOI: 10.3390/brainsci14050413
  83. 83. de Melo ASLF, Lima JLD, Malta MCS, Marroquim NF, Moreira ÁR, de Almeida Ladeia I, Dos Santos Cardoso F, Gonçalves DB, Dutra BG, Dos Santos JCC. The role of microglia in prion diseases and possible therapeutic targets: A literature review. Prion. 2021;15(1):191–206. DOI: 10.1080/19336896.2021.1991771
  84. 84. Carroll JA, Chesebro B. Neuroinflammation, microglia, and cell-association during prion disease. Viruses. 2019;11(1):65. DOI: 10.3390/v11010065
  85. 85. Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimer’s & Dementia (New York, N.Y.). 2018;4:575–590. DOI: 10.1016/j.trci.2018.06.014
  86. 86. Makarava N, Safadi T, Bocharova O, Mychko O, Pandit NP, Molesworth K, Baskakov IV et al. Reactive microglia partially envelop viable neurons in prion diseases. The Journal of Clinical Investigation. 2024;134(23):e181169
  87. 87. Zhang W, Xiao D, Mao Q, et al. Role of neuroinflammation in neurodegeneration development. Signal Transduction and Targeted Therapy. 2023;8:267
  88. 88. Wang Y, Hartmann K, Thies E, Mohammadi B, Altmeppen H, Sepulveda-Falla D, Krasemann S. Loss of homeostatic microglia signature in prion diseases. Cells. 2022;11(19):2948
  89. 89. Moon JH, Hong JM, Park SY. Calcineurin activation by prion protein induces neurotoxicity via mitochondrial reactive oxygen species. Oxidative Medicine and Cellular Longevity. 2021;2021:5572129. DOI: 10.1155/2021/5572129
  90. 90. Aguzzi A, Zhu C. Microglia in prion diseases. The Journal of Clinical Investigation. 2017;127(9):3230–3239
  91. 91. Boje KM, Arora PK. Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Research. 1992;587(2):250–256
  92. 92. Simpson DSA, Oliver PL. ROS generation in microglia: Understanding oxidative stress and inflammation in neurodegenerative disease. Antioxidants (Basel, Switzerland). 2020;9(8):743. DOI: 10.3390/antiox9080743
  93. 93. Bourgognon JM, Spiers JG, Robinson SW, Scheiblich H, Glynn P, Ortori C, Steinert JR et al. Inhibition of neuroinflammatory nitric oxide signaling suppresses glycation and prevents neuronal dysfunction in mouse prion disease. Proceedings of the National Academy of Sciences. 2021;118(10):e2009579118
  94. 94. Moore S, Meschkat M, Ruhwedel T, et al. A role of oligodendrocytes in information processing. Nature Communications. 2020;11:5497
  95. 95. Bokulic Panichi L, Stanca S, Dolciotti C, Bongioanni P. The role of oligodendrocytes in neurodegenerative diseases: Unwrapping the layers. International Journal of Molecular Sciences. 2025;26(10):4623. DOI: 10.3390/ijms26104623
  96. 96. Sponne I, Fifre A, Koziel V, Kriem B, Oster T, Olivier JL, Pillot T. Oligodendrocytes are susceptible to apoptotic cell death induced by prion protein‐derived peptides. Glia. 2004;47(1):1–8
  97. 97. Kirby L, Jin J, Cardona JG, Smith MD, Martin KA, Wang J, Strasburger H, Herbst L, Alexis M, Karnell J, Davidson T, Dutta R, Goverman J, Bergles D, Calabresi PA. Oligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination. Nature Communications. 2019;10(1):3887. DOI: 10.1038/s41467-019-11638-3
  98. 98. Dar NJ, Bhat JA, John U, Bhat SA. Neuroglia in neurodegeneration: Exploring glial dynamics in brain disorders. Neuroglia. 2024;5(4):488–504. DOI: 10.3390/neuroglia5040031
  99. 99. Magni G, Riboldi B, Ceruti S. Human glial cells as innovative targets for the therapy of central nervous system pathologies. Cells. 2024;13(7):606. DOI: 10.3390/cells13070606
  100. 100. Andreasson KI, Bachstetter AD, Colonna M, Ginhoux F, Holmes C, Lamb B, Van Eldik LJ, et al.. Targeting innate immunity for neurodegenerative disorders of the central nervous system. Cold Spring Harbor Perspectives in Biology. 2016;138(5):653–693
  101. 101. Moussa N, Dayoub N. Exploring the role of COX-2 in Alzheimer’s disease: Potential therapeutic implications of COX-2 inhibitors. Saudi Pharmaceutical Journal. 2023;31(9):101729. DOI: 10.1016/j.jsps.2023.101729
  102. 102. PL M, EG M. NSAIDs and Alzheimer disease: Epidemiological, animal model and clinical studies. Neurobiology of Aging. 2007;28(5):639–647. DOI: 10.1016/j.neurobiolaging.2006.03.013
  103. 103. Márquez Loza A, Elias V, Wong CP, Ho E, Bermudez M, Magnusson KR. Effects of ibuprofen on cognition and NMDA receptor subunit expression across aging. Neuroscience. 2017;344:276–292. DOI: 10.1016/j.neuroscience.2016.12.041
  104. 104. Meinert ADAPTRG, L. C, McCaffrey LD, Breitner JC. Alzheimer’s Disease Anti-inflammatory Prevention Trial: Design, methods, and baseline results. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. 2009;5(2):93–104. DOI: 10.1016/j.jalz.2008.09.004
  105. 105. Qin J, Ma Z, Chen X, Shu S. Microglia activation in central nervous system disorders: A review of recent mechanistic investigations and development efforts. Frontiers in Neurology. 2023;14:1103416. DOI: 10.3389/fneur.2023.1103416
  106. 106. Shaftel SS, Carlson TJ, Olschowka JA, Kyrkanides S, Matousek SB, O’Banion MK. Chronic interleukin-1beta expression in mouse brain leads to leukocyte infiltration and neutrophil-independent blood brain barrier permeability without overt neurodegeneration. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2007;27(35):9301–9309. DOI: 10.1523/JNEUROSCI.1418-07.2007
  107. 107. Shaftel SS, Griffin WS, O’Banion MK. The role of interleukin-1 in neuroinflammation and Alzheimer disease: An evolving perspective. Journal of Neuroinflammation. 2008;5:7. DOI: 10.1186/1742-2094-5-7
  108. 108. GuoYan L, ShuQin Z, HuiYang Q, MengYing C, HongWei R, Hong S. IL-8 and IL-1β in the cerebrospinal fluid of patient with Creutzfeldt-Jakob disease: A case report. Clinical Case Reports. 2025;13(5):e70508. DOI: 10.1002/ccr3.70508
  109. 109. Onuska KM. The dual role of microglia in the progression of Alzheimer’s disease. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2020;40(8):1608–1610. DOI: 10.1523/JNEUROSCI.2594-19.2020
  110. 110. He C, Chen B, Yang H, Zhou X. The dual role of microglia in Alzheimer’s disease: From immune regulation to pathological progression. Frontiers in Aging Neuroscience. 2025;17:1554398. DOI: 10.3389/fnagi.2025.15543
  111. 111. Deming Y, Li Z, Benitez BA, Cruchaga C. Triggering receptor expressed on myeloid cells 2 (TREM2): A potential therapeutic target for Alzheimer disease? Expert Opinion on Therapeutic Targets. 2018;22(7):587–598. DOI: 10.1080/14728222.2018.1486823
  112. 112. Qu W, Li L. Microglial TREM2 at the intersection of brain aging and Alzheimer’s disease. The Neuroscientist: A Review Journal Bringing Neurobiology, Neurology and Psychiatry. 2023;29(3):302–316. DOI: 10.1177/10738584211040786
  113. 113. Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I. Disease-associated microglia: A universal immune sensor of neurodegeneration. Cell. 2018;173(5):1073–1081
  114. 114. Long H, Simmons A, Mayorga A, Burgess B, Nguyen T, Budda B, Rychkova A, Rhinn H, Tassi I, Ward M, Yeh F, Schwabe T, Paul R, Kenkare-Mitra S, Rosenthal A. Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer’s disease. Alzheimer’s Research & Therapy. 2024;16(1):235. DOI: 10.1186/s13195-024-01599-1
  115. 115. Chitu V, Gokhan Ş, Nandi S, Mehler MF, Stanley ER. Emerging roles for CSF-1 receptor and its ligands in the nervous system. Trends in Neurosciences. 2016;39(6):378–393. DOI: 10.1016/j.tins.2016.03.005
  116. 116. Hu B, Duan S, Wang Z, Li X, Zhou Y, Zhang X, Zheng H et al. Insights into the role of CSF1R in the central nervous system and neurological disorders. Frontiers in Aging Neuroscience. 2021;13:789834
  117. 117. De I, Nikodemova M, Steffen MD, Sokn E, Maklakova VI, Watters JJ, Collier LS. CSF1 overexpression has pleiotropic effects on microglia in vivo. Glia. 2014;62(12):1955–1967
  118. 118. Henry RJ, Ritzel RM, Barrett JP, Doran SJ, Jiao Y, Leach JB, Szeto GL, Wu J, Stoica BA, Faden AI, Loane DJ. Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2020;40(14):2960–2974. DOI: 10.1523/JNEUROSCI.2402-19.2020
  119. 119. Han J, Chitu V, Stanley ER, Wszolek ZK, Karrenbauer VD, Harris RA. Inhibition of colony stimulating factor-1 receptor (CSF-1R) as a potential therapeutic strategy for neurodegenerative diseases: Opportunities and challenges. Cellular and Molecular Life Sciences. 2022;79(4):219. DOI: 10.1007/s00018-022-04225-1
  120. 120. Race B, Williams K, Baune C, Striebel JF, Long D, Thomas T, Lubke L, Chesebro B, Carroll JA. Microglia have limited influence on early prion pathogenesis, clearance, or replication. PloS One. 2022;17(10):e0276850. DOI: 10.1371/journal.pone.0276850
  121. 121. Miao J, Ma H, Yang Y, Liao Y, Lin C, Zheng J, Yu M, Lan J. Microglia in Alzheimer’s disease: Pathogenesis, mechanisms, and therapeutic potentials. Frontiers in Aging Neuroscience. 2023;15:1201982. DOI: 10.3389/fnagi.2023.1201982
  122. 122. Kim K, Lee SG, Kegelman TP, et al. Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: Opportunities for developing novel therapeutics. Journal of Cellular Physiology. 2011;226(10):2484–2493. DOI: 10.1002/jcp.22609
  123. 123. Lee SG, Su ZZ, Emdad L, Gupta P, Sarkar D, Borjabad A, Volsky DJ, Fisher PB. Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes. Journal of Biological Chemistry. 2008;283(19):13116–13123. DOI: 10.1074/jbc.M707697200
  124. 124. Fontana AC, Fox DP, Zoubroulis A, Mortensen OV, Raghupathi R. Neuroprotective effects of the glutamate transporter activator (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) following traumatic brain injury in the adult rat. Journal of Neurotrauma. 2016;33(11):1073–1083. DOI: 10.1089/neu.2015.4079
  125. 125. Kong Q, Chang LC, Takahashi K, Liu Q, Schulte DA, Lai L, Ibabao B, Lin Y, Stouffer N, Das Mukhopadhyay C, Xing X, Seyb KI, Cuny GD, Glicksman MA, Lin CL. Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection. Journal of Clinical Investigation. 2014;124(3):1255–1267. DOI: 10.1172/JCI66163
  126. 126. Weller ML, Stone IM, Goss A, Rau T, Rova C, Poulsen DJ. Selective overexpression of excitatory amino acid transporter 2 (EAAT2) in astrocytes enhances neuroprotection from moderate but not severe hypoxia-ischemia. Neuroscience. 2008;155(4):1204–1211. DOI: 10.1016/j.neuroscience.2008.05.059
  127. 127. Jain M, Singh MK, Shyam H, Mishra A, Kumar S, Kumar A, Kushwaha J. Role of JAK/STAT in the neuroinflammation and its association with neurological disorders. Annals of Neurosciences. 2021;28(3-4):191–200
  128. 128. Haim LB, Ceyzériat K, Carrillo-de Sauvage MA, Aubry F, Auregan G, Guillermier M, Escartin C et al. The JAK/STAT3 pathway is a common inducer of astrocyte reactivity in Alzheimer’s and Huntington’s diseases. Journal of Neuroscience. 2015;35(6):2817–2829
  129. 129. Reichenbach N, Delekate A, Plescher M, Schmitt F, Krauss S, Blank N, Halle A, Petzold GC. Inhibition of Stat3-mediated astrogliosis ameliorates pathology in an Alzheimer’s disease model. EMBO Molecular Medicine. 2019;11(2):e9665. DOI: 10.15252/emmm.201809665
  130. 130. Raible DJ, Frey LC, Brooks-Kayal AR. Effects of JAK2-STAT3 signaling after cerebral insults. Jak-stat. 2014;3(2):e29510. DOI: 10.4161/jkst.29510
  131. 131. An JY, Pang HG, Huang TQ, Song JN, Li DD, Zhao YL, Ma XD. AG490 ameliorates early brain injury via inhibition of JAK2/STAT3-mediated regulation of HMGB1 in subarachnoid hemorrhage. Experimental and Therapeutic Medicine. 2018;15(2):1330–1338. DOI: 10.3892/etm.2017.5539
  132. 132. Chen KS, Koubek EJ, Sakowski SA, Feldman EL. Stem cell therapeutics and gene therapy for neurologic disorders. Neurotherapeutics. 2024;21(4):e00427
  133. 133. Kim SU, Lee HJ, Kim YB. Neural stem cell-based treatment for neurodegenerative diseases. Neuropathology: Official Journal of the Japanese Society of Neuropathology. 2013;33(5):491–504. DOI: 10.1111/neup.12020
  134. 134. Wolfe CM, Fitz NF, Nam KN, Lefterov I, Koldamova R. The role of APOE and TREM2 in Alzheimer’s disease-current understanding and perspectives. International Journal of Molecular Sciences. 2018;20(1):81. DOI: 10.3390/ijms20010081
  135. 135. Lin YT, Seo J, Gao F, Feldman HM, Wen HL, Penney J, Cam HP, Gjoneska E, Raja WK, Cheng J, Rueda R, Kritskiy O, Abdurrob F, Peng Z, Milo B, Yu CJ, Elmsaouri S, Dey D, Ko T, Yankner BA, Tsai LH. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron. 2018;98(6):1141–1154.e7. Epub 2018 May 31. Erratum in: Neuron. 2018 Jun 27;98(6):1294. doi: 10.1016/j.neuron.2018.06.011. DOI: 10.1016/j.neuron.2018.05.008
  136. 136. Teter B, Campagna J, Zhu C, McCauley GE, Spilman P, Kohn DB, John V (2024). Successful gene editing of apolipoprotein E4 to E3 in brain of Alzheimer model mice after a single IV Dose of Synthetic Exosome-Delivered CRISPR. bioRxiv, 2024–04
  137. 137. Garcia-Reitboeck P, Phillips A, Piers TM, Villegas-Llerena C, Butler M, Mallach A, Pocock JM et al. Human induced pluripotent stem cell-derived microglia-like cells harboring TREM2 missense mutations show specific deficits in phagocytosis. Cell Reports. 2018;24(9):2300–2311
  138. 138. Piers TM, Cosker K, Mallach A, Johnson GT, Guerreiro R, Hardy J, Pocock JM. A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC-derived microglia. The FASEB Journal. 2020;34(2):2436–2450. DOI: 10.1096/fj.201902447R
  139. 139. Hastings N, Kuan WL, Osborne A, Kotter MRN. Therapeutic potential of astrocyte transplantation. Cell Transplantation. 2022;31:9636897221105499. DOI: 10.1177/09636897221105499
  140. 140. Krencik R, Weick J, Liu Y, et al. Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nature Biotechnology. 2011;29:528–534
  141. 141. Armijo E, Edwards G, Flores A, Vera J, Shahnawaz M, Moda F, Gonzalez C, Sanhueza M, Soto C. Induced pluripotent stem cell-derived neural precursors improve memory, synaptic and pathological abnormalities in a mouse model of Alzheimer’s disease. Cells. 2021;10(7):1802. DOI: 10.3390/cells10071802
  142. 142. Ifediora N, Canoll P, Hargus G. Human stem cell transplantation models of Alzheimer’s disease. Frontiers in Aging Neuroscience. 2024;16:1354164. DOI: 10.3389/fnagi.2024.1354164
  143. 143. Windrem MS, Schanz SJ, Zou L, Chandler-Militello D, Kuypers NJ, Nedergaard M, Goldman SA. Human glial progenitor cells effectively remyelinate the demyelinated adult brain. Cell Reports. 2020;31(7):107658
  144. 144. Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, Colonna M et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell. 2015;160(6):1061–1071

Written By

Saima Zafar, Urwah Rasheed and Inga Zerr

Submitted: 09 October 2025 Reviewed: 15 October 2025 Published: 25 February 2026

© 2026 The Author(s). Licensee IntechOpen. This content is distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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