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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by extracellular amyloid beta (Aβ) plaques, intracellular neurofibrillary tangles (NFTs), astrogliosis, loss of neurons, and cognitive decline. In this narrative review, we explore astrocytes’ dual role in the healthy brain and the brain with AD, reflecting on the available human studies and animal models. Astrocytes are multifunctional regulators of brain homeostasis and neuronal activity within the central nervous system (CNS). These highly plastic cells undergo morphological and functional changes in response to the progression of AD, and exhibit dynamic, stage-dependent phenotypes. In the early stage of AD, astrocytes adopt a predominantly neuroprotective A2 phenotype, marked by enhanced glycolysis, Aβ clearance, anti-inflammatory signaling, and synaptic support. At the intermediate stage, they shift toward an inflammatory phenotype, which consequently impairs metabolism and neurotransmitter uptake. In the late stage of AD, the A1 phenotype, characterized by inflammatory cytokine secretion, complement activation, Ca dysregulation, and mitochondrial toxicity, exacerbates AD progression. Thus, the balance between these subtypes can significantly influence the disease’s trajectory, with A1 astrocytes contributing to neurotoxicity and A2 astrocytes providing neuroprotection, especially in the early stages.

Keywords

astrocytes Alzheimer’s disease A1 phenotype A2 phenotype apoptosis

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease defined by multifactorial etiology and distinct neuropathological features. AD represents 60% to 70% of all dementia cases in those aged 65 and older.¹ This disease manifests as a decline in cognitive abilities, particularly in memory, language, and executive functions, resulting in diminished functional independence and significant behavioral changes.²

Despite extensive research in recent decades, the exact mechanisms of AD remain unclear, and effective treatments have yet to be developed. Current treatments merely offer symptomatic relief without altering the disease course and reveal unbearable side effects.³

Pathologically, AD is characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein. They can disrupt neuronal activity and contribute to neuroinflammation and disease progression^4,5 and consequently lead to synaptic damage and neuronal loss.^6,7

Recently, astrocytes’ role in the pathophysiology of AD has attracted considerable interest. This review examines the existing literature to explain the complex mechanisms through which astrocytes contribute to AD pathology. Below, we compare astrocytes’ roles in the healthy and AD brains, focusing on possible molecular mechanisms.

Methods

A literature review was conducted using PubMed, Scopus, Medline, Science Direct, and Google Scholar search engines. We included references up to Jun 2025 with “Astrocyte” and “Alzheimer’s disease” as the primary keywords used for screening to identify available human studies and animal models of AD. To limit the literature to the scope of this review, those articles written in languages other than English were excluded. We discovered additional articles beyond the initial search from key studies cited in other articles. A total of 130 relevant articles were included based on their subject matter.

Astrocytes Function in the Healthy Brain

Astrocytes are multifunctional cells that maintain homeostasis and support neural functions in the central nervous system (CNS).⁸ They are characterized by significant heterogeneity in morphology, molecular profiles, and functional capabilities, which vary based on their specific brain regions and status. There are many astrocytic subpopulations characterized by morphology,⁹ including protoplasmic spherical,^10,11 fibrous elongated,¹¹ Pituicytes (irregularly shaped, with many processes),^12,13 and Bergmann Glia (with long radial structure extensions).^11,14 Since these subpopulations are specified by brain anatomic regions, this is outside the scope of this review. Here, we compare the functionality of these cells in healthy physiological status and AD.

Astrocytes communicate with each other and neurons through gap junctions and chemical signaling. This intercellular networking allows them to coordinate responses to neuronal activity and maintains overall homeostasis in the CNS.⁸ They also interact with other glial cells, like microglia and oligodendrocytes, as well as peripheral immune cells, thereby facilitating a comprehensive response to various stimuli.¹⁵

They are essential for neuronal network integrity, ion and pH balance, and extracellular matrix stability.⁸ As integral components of the blood-brain barrier (BBB), astrocytes offer neurotrophic support, nutrient supply, and contribute to the glymphatic system by removing waste products from the brain.¹⁶ They also act alongside microglia as the initial defense system against harmful agents.¹⁶ Besides, astrocytes interact with neurons and blood vessels, forming part of the neurovascular unit.¹⁷ By creating the glia limitans, astrocytes not only offer structural support to the CNS but also actively engage in regulating the BBB. Their chemosensory capabilities enable them to contribute significantly to the body’s overall equilibrium, particularly in regulating energy and stabilizing blood pH concentrations.^18,19

They regulate cerebral blood flow in response to neuronal activity by releasing vasoactive substances such as prostaglandins and induce vasodilation.^20
-22 Also, these glia cells take up excess K⁺ released during neuronal firing, to prevent hyperexcitability.⁸ Additionally, they uptake and recycle neurotransmitters, especially glutamate, via specific transporters such as GLT-1. This function helps prevent excitotoxicity and promotes effective synaptic transmission.²³

Astrocytes are pivotal in providing metabolic substrates to neurons.²⁴ They take glucose from the bloodstream through glucose transporters, particularly GLUT-2 in the hypothalamus, and convert it into lactate via glycolysis, which is further shuttled to neurons via the astrocyte-neuron lactate shuttle (ANLS)²⁵ serving as an essential energy source, especially during times of neural hyperactivity.^26,27 Also, lactate is now recognized as a signaling molecule in the brain,^28
-30 which influences neurophysiological processes. Besides, lactate supports synaptic plasticity and memory³¹ by affecting the N-methyl-D-aspartate (NMDA) receptor activity and long-term potentiation (LTP).³² It also offers neuroprotection by maintaining energy during stress and boosting blood flow through inhibiting prostaglandin transporter and increasing prostaglandin E2 signaling, and vasodilation.³³ All these highlight lactate’s importance in energy metabolism, neurovascular regulation and cell communication, emphasizing its key roles to brain health.³⁴

Additionally, astrocytes store glycogen as an energy source,⁸ and cooperate in lipid transport by expressing fatty acid translocase, CD36, and apolipoprotein E (ApoE), to regulate energy balance.^35
-37

Besides their energy-balancing role, astrocytes exhibit neuroprotective roles by releasing neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and S100 calcium-binding protein B (S100B),^38,39 and support neuronal survival and function.⁴⁰ Thus, they underlie synaptic plasticity and boost the brain’s cognitive flexibility by releasing BDNF, S100B, glutamate, D-serine, and adenosine triphosphate (ATP).^15,41

Another important role that should be noticed is clearing excess glutamate from the synaptic cleft, preventing excitotoxicity, which can potentially impair cognitive function.⁴² Particularly in the presence of Aβ, aberrantly elevated astrocytic Ca²⁺ levels lead to increased glutamate release and excitotoxicity, possibly contributing to synaptic loss and memory impairment.⁴³ Although dysregulation in astrocytic calcium ion (Ca²⁺) levels and the upregulation of adenosine A2 receptors (A2Rs) could potentiate mechanisms associated with active forgetting^43
-46 a mechanism for removing irrelevant or outdated memories by weakening synaptic connections.⁴⁶

Furthermore, gliotransmitters released by astrocytes, including ATP, D-serine, and L-lactate, can significantly improve synaptic transmission and promote LTP.^47,48

These findings highlight the interdependence between glial cells and neurons in maintaining optimal brain function and neuronal health.

Astrocyte Phenotypes in Alzheimer’s Disease

Astrocytes undertake profound functional and morphological changes in AD, which evolve with disease progression, impacting neuronal viability, neuroinflammation, and the integrity of synaptic and vascular networks.^49,50 Understanding their complete functions is still in its early stages.

A1 Astrocytes

A1 astrocytes are characterized by a lengthy and thickened dendritic tree and enlarged cell bodies. Their processes become more complex, often with more bifurcations. They upregulate glial fibrillary acidic protein (GFAP), S100b, and complement component 3 (C3), promoting pro-inflammatory reactions and the release of neurotoxic agents,^51,52 which disrupts synapse formation and maintenance.^53,54 They also secrete tumor necrosis factor-alpha (TNF-α), interleukin-1 alpha (IL-1α), and complement component 1q (C1q),⁵⁰ by which A1 astrocytes exhibit neurotoxic properties, contributing to neuronal death and exacerbating neurodegeneration.⁵⁰

Meanwhile, dysregulated calcium signaling in A1 astrocytes impairs their response to neuronal activity and disrupts CNS homeostasis, and contributes to excitotoxicity and neuronal damage.⁵⁵ Besides, A1 astrocytes may impair the glymphatic system’s function, which is essential for clearing waste products, including Aβ peptides, and lead to the build-up of neurotoxic substances in the brain.⁵⁵

A2 Astrocytes

These cells have hypertrophied somas and exhibit only a limited number of processes.⁵⁶ They are involved in promoting repair and reducing inflammation^40,57 by expressing genes promoting anti-inflammatory responses and neurotrophic factors, such as BDNF, insulin-like growth factor 1 (IGF-1), transforming growth factor-beta (TGF-β),^58
-60 S100 calcium binding protein A10 (S100A10), and pentraxin 3.⁵⁶ They can also release anti-inflammatory cytokines, like interleukin-10 (IL-10), that help counteract the effects of pro-inflammatory mediators released by activated microglia.⁵¹ They also play a role in repairing and maintaining the BBB, helping restore its integrity and preventing further neuronal damage,^60,61 and facilitate the removal of waste products from the brain, including Aβ peptides.⁵⁵

The third phenotype, with GFAP-high state identified in AD, is the disease-associated astrocyte (DAA), which appears early in the disease (before cognitive decline) and grows in prevalence as pathology progresses. DAAs are primarily localized around amyloid plaques within hippocampal regions and subiculum, and exhibit overlapping gene expression patterns with microglia, indicating a shared inflammatory response program across glial cells during disease linked to the complement cascade, endocytosis, and aging.^55,56,62 They exhibit a mixed expression profile, showing some overlap with both A1 and A2 phenotype markers, indicating a complex and dynamic state of reactivity.⁵⁹ Initially, DAAs may exert protective roles, potentially isolating pathological amyloid, but over time, they may become neurotoxic, featuring increased inflammatory gene expression such as SerpinA3N, and impair plaque clearance.⁶²

It should be noticed that some believe that there is no single reactive astrocyte type, nor do they polarize into binary phenotypes like neurotoxic-neuroprotective, or A1-A2.⁵¹ Instead, reactive astrocytes adopt various states depending on the context, with only a few common changes shared across states. Therefore, astrocyte phenotypes should be defined using more molecular markers and functional assessments, ideally in vivo, instead of relying solely on GFAP and morphology.⁵¹

Moreover, considering the complexity of AD and the brain microenvironment, it is better to evaluate the astrocyte phenotypes in different stages of the disease.

Polarization of A1 to A2 Astrocytes in the Stages of AD

Early Stage of AD

There is limited evidence on AD stages and alterations in astrocyte phenotype, which needs further investigation. However, available evidence shows that A2 astrocytes appear in the early stages of AD, particularly in response to initial neuronal stress or injury, to promote recovery and protect against neurodegeneration,⁶⁰ although their effectiveness may diminish as the disease progresses.^55,58

In animal models, AD studies on the early stage, reveal several astrocytic changes. For example, APP/PS1 mice show decreased astrocyte volume and surface area, along with fewer protoplasmic processes in the medial prefrontal cortex and hippocampus (Table 1), before overt plaque deposition, suggesting a very early role in pathogenesis.^63
-66

Table 1.

Summary of Original Studies Investigating Astrocyte Alterations Across Alzheimer’s Disease Models and Stages.

Study (y)	Model system	AD stage	Astrocyte changes	Neuronal effect
Söllvander et al (2016)	In vitro + tg-ArcSwe mouse (12-14 mo)	Early → late	Aβ uptake, lysosomal dysfunction, release of truncated Aβ in vesicles	Induces neuronal apoptosis via astrocyte-derived vesicles
Shah et al (2022)	AppNL-F mouse (3 mo) + human	Early	↓ Ca²⁺ signaling, astrocytic silencing restored via DREADDs	↓ Neuronal hyperactivity, preserved network function
Jiwaji et al (2022)	APP/PS1 + MAPTP301S mice	Early → late	Astrocytic Nrf2 reprogramming restores proteostasis	↓ Aβ/pTau, improved synaptic and cognitive function
Kamphuis et al (2012)	APPswePS1dE9 mouse	Intermediate → late	Hypertrophic non-proliferative astrogliosis	Associated with a chronic plaque environment
Kim et al (2024)	APP/PS1 + in vitro	Early → late	↑ LC3B autophagy clears Aβ	Cognitive protection via synaptic rescue
Lian et al (2016)	APP/PS1 + primary astrocytes	Intermediate → late	NF-κB activation, ↑ C3 expression	Impaired microglial Aβ clearance, inflammation
Portal et al (2024)	AppNL-F mouse	Early	Astrocytic GABA release (via MAO-B)	Synaptic silencing, impaired information processing
Sanchez-Mico et al (2021)	APP/PS1 + in vitro	Intermediate	↓ Synaptic phagocytosis, ↓ phagocytosis receptors such as Mertk/Megf10	Dystrophic synapse accumulation
Hendrix et al (2021)	BRI-Aβ42 mouse + human	Intermediate	GLUT1 mislocalization from astrocytic membranes	↓ Glucose uptake, impaired brain energy metabolism
Maté de Gérando et al (2021)	Tau-injected mice + Thy-Tau22	Early → Intermediate	Astrocytic tau uptake (soluble) → cell death	Contributes to tau spread and local neurodegeneration
Richetin et al (2020)	AAV-3R Tau in mice + human	Intermediate	Mitochondrial fragmentation, ↓ neurogenesis	PV + interneuron loss, memory deficits
St-Pierre et al (2023)	APP-PS1 + human	Late	↑ Lysosomes, lipid bodies, “dark” astrocytes	Perisynaptic and perivascular stress environment
Kulijewicz-Nawrot et al (2012)	3×Tg-AD mice	Early → late	Cytoskeletal atrophy in mPFC astrocytes	Disrupted astrocyte-neuron interaction
Yeh et al (2011)	3×Tg-AD mice	Early	Astrocytic atrophy in EC before plaque/tau pathology	Potential early synaptic vulnerability
Beauquis et al (2014)	PDAPP-J20 mice	Early	Astrocytic loss and simplification	Cognitive deficits before Aβ deposition
Hou et al (2011)	In vitro	-	↑ GFAP, IL-1β, ↓ viability under Aβ₄₂	Neuroinflammation, astrocytic stress
Watanabe et al (2015)	In vitro + human	Intermediate → late	IGFBP-3 release via calcineurin → tau phosphorylation	Neuronal toxicity through IGF-I inhibition
Liang et al (2020)	5xFAD + in vitro	Intermediate → late	↑ APP/BACE1 in astrocytes → Aβ production	Autocrine amplification of amyloidosis
Nikkar et al (2022)	Aβ-injected rats + JQ1	Early	Astrocyte inhibition worsens pathology, JQ1 protective via CREB	Memory recovery depends on astrocyte function
Han et al (2024)	Senescent astrocytes + AD mice	Aging	SerpinA3N-driven SASP phenotype	Inflammatory environment, neuron death
Saha et al (2020)	In vitro + rat cortex	Early	Aβ activates JNK/p38 MAPK → GFAP ↑, proliferation	Potential contribution to early astrogliosis
Xu et al (2021)	APP/PS1 + YAP knockout	Early	YAP prevents astrocyte senescence via CDK6	YAP rescue improves cognition via astrocyte support
Le Douce et al (2020)	3×Tg-AD + human + AAV	Early	↓ PHGDH → ↓ L-serine/D-serine in astrocytes	NMDAR hypofunction, impaired LTP, and memory
Li et al (2024)	Aβ-injected mice + primary astrocytes	Early → intermediate	Aβ triggers mitochondrial fragmentation via DRP1 in astrocytes → ↑ ROS, ↓ ATP, ↓ phagocytosis	Impaired neuronal support, increased Aβ accumulation, and worsened neuronal viability
Martínez-Frailes et al (2019)	J20 × P2X7R-EGFP mice + in vitro	Intermediate → late	Astrocyte-secreted pro-inflammatory signals (via P2X7R activation) modulate microglial phagocytosis	Elevated ROS, impaired Aβ clearance, and potential neuroinflammation
Lee et al (2011)	APP/PS1ΔE9 mice (3-12 mo)	Early → late	P2X7R upregulated in astrocytes and microglia near plaques	Associated with neuronal damage and oxidative stress prior to extensive plaque deposition
Doroszkiewicz et al (2024)	Human CSF (MCI, AD, controls)	Early → late	↑ NGAL and CXCL11 levels (glia-derived); CXCL11 peaks in MCI; sTREM1 peaks early; sTREM2 increases with disease	Strong correlation with tau/pTau; early markers (NGAL, CXCL11) outperform Aβ_1-42 in MCI diagnosis; sTREM2 may reflect delayed microglial neuroprotection
Rodriguez-Vieitez et al (2016)	Human ADAD (PET imaging)	Preclinical → late	¹¹C-DED PET signal (astrocytosis) peaks ~17 y before onset, then declines	Early astrocyte activation precedes amyloid and hypometabolism; a possible early protective or compensatory role
Schöll et al (2015)	Human ADAD (PET imaging)	Preclinical	Early regional astrocytosis (¹¹C-DED ↑) before amyloid or metabolic change	Indicates astrocytes as very early responders in AD pathogenesis
Rostami et al (2021)	hiPSC co-culture (astrocytes, microglia, neurons)	-	Astrocytes accumulate Aβ and α-synuclein; microglia remove aggregates via TNTs	Interacellular transfer of aggregates reduces astrocyte stress and improves neuronal integrity
Olabarria et al (2010)	3×Tg-AD mice	Early → late	Early astrocytic atrophy in DG; late-stage plaque-associated hypertrophy	Early atrophy may impair support; later reactive hypertrophy occurs near plaques
Elahi et al (2020)	Human plasma biomarker study	Early → late	Plasma GFAP is elevated in early-onset AD; less so in LOAD	GFAP correlated with cognitive decline and brain atrophy; suggesting astrocyte dysfunction contributes to neurodegeneration
Carter et al (2012)	Human PET (¹¹C-DED, PiB, FDG)	Prodromal	↑ Astrocytic MAO-B signal (via ¹¹C-DED) before amyloid or glucose metabolism changes	Suggests astrocytosis as a prodromal event, preceding conventional biomarkers

Abbreviations: AD, Alzheimer’s disease; ADAD, autosomal dominant Alzheimer’s disease; Aβ, amyloid beta; APP, amyloid-beta protein precursor; Ca²⁺, calcium ion; CREB, cAMP response element-binding protein; CXCL11, chemokine (C-X-C motif) ligand 11; DG, dentate gyrus; DREADDs, hM3Dq designer receptors exclusively activated by designer drugs; DRP1, dynamin-related protein 1; EC, entorhinal cortex; FDG, fluorodeoxyglucose; GFAP, glial fibrillary acidic protein; hM3Dq, human muscarinic receptor type 3 DREADD; hiPSC, human-induced pluripotent stem cell; IGF, insulin-like growth factor; IGFBP-3, insulin-like growth factor-binding protein 3; JNK, c-Jun N-terminal kinase; LC3B, microtubule-associated protein 1A/1B-light chain 3B; LOAD, late-onset Alzheimer’s disease; MAO-B, monoamine oxidase type B; MAPK, mitogen-activated protein kinase; MAPT, microtubule-associated protein tau; MCI, mild cognitive impairment; Megf10, multiple EGF-like domains 10; mPFC, medial prefrontal cortex; NGAL, neutrophil gelatinase-associated lipocalin; NMDAR, N-methyl-D-aspartate receptor; Nrf2, nuclear factor erythroid 2-related factor 2; PET, positron emission tomography; PHGDH, 3-phosphoglycerate dehydrogenase; PiB, Pittsburgh compound B; PS1, presenilin 1; pTau, phosphorylated tau; PV, parvalbumin; P2X7R, P2X7 receptor; ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype; sTREM1/2, soluble triggering receptor expressed on myeloid cells 1 and 2; TNTs, tunneling nanotubes; YAP, yes-associated protein.

Also, astrocytes typically exhibit mild reactive astrogliosis marked by expression of GFAP,⁶⁷ without proliferative scar formation.^68
-70 In human studies, ^11C-DED PET imaging in AD patients shows that astrocytosis is detected as early as the preclinical stage, peaking ~17 years before clinical onset (Table 1), suggesting a protective or compensatory role in early disease.^69,70 In patients with AD disease, Plasma biomarkers such as GFAP and neurofilament light chain (NfL) are elevated in early-onset AD and correlate with cognitive decline,⁷¹ reflecting astrocyte involvement.

Another hallmark of early-stage astrocyte response is an increase in glycolytic activity. Astrocytes increase lactate production and transport it to neurons via the astrocyte-neuron lactate shuttle (ANLS), thereby compensating for neuronal hypometabolism and preserving synaptic activity.²⁵ At this stage, astrocytes actively clear Aβ through endocytosis and enzymatic degradation, utilizing insulin-degrading enzyme, neprilysin, and endothelin-converting enzymes 1 and 2 (ECE1 and ECE2). This clearance is critical in mitigating early Aβ accumulation and toxicity.^64,72
-75 Attempts to inhibit astrocyte metabolism (eg, fluorocitrate treatment) in the early stage of the AD animal model resulted in memory impairments and increased TNF-α, indicating astrocytes’ protective roles in the initial stages.^76,77

A2 astrocytes also secrete anti-inflammatory cytokines and neurotrophic factors in early AD stages, helping modulate the immune environment and promote neuronal survival.^78
-82

Recent studies indicate that the astroglial endocannabinoid system significantly modulates neurobiological processes related to cognitive function in AD, through cannabinoid receptors of CB1 and CB2.⁸³ Endocannabinoids exhibit neuroprotective effects, potentially shielding neurons from Aβ toxicity and tau pathology⁸⁴ by regulating the astrocytes’ glutamate uptake and release,⁸⁵ and also astrocytic energy metabolism.⁸⁶

Moreover, Mitochondrial dysfunction and oxidative stress are evident; for example, Aβ-injected mice and primary astrocytes show mitochondrial fragmentation, leading to increased ROS, reduced ATP, and impaired neuronal support.⁸⁷ In Tau-injected mice, astrocytic tau uptake contributes to local neurodegeneration and neuronal loss^88,89 (Table 1).

Some studies on transgenic mice, such as App/NLF mice, showed reduced Ca²⁺ signaling and silenced astrocytic activity.⁹⁰ While tg-ArcSwe mice exhibited Aβ uptake, lysosomal dysfunction, and the release of truncated Aβ into vesicles, and neuronal apoptosis.⁸² Also, astrocytic nuclear factor erythroid 2-related factor 2 (Nrf2) reprogramming in APP/PS1 + MAPTP301S mice restores proteostasis, reducing Aβ/phosphorylated tau (pTau) accumulation and improving synaptic and cognitive function⁸³ (Table 1).

Taken together, these studies indicate that in the early stage of AD, astrocytes actively attempt to maintain homeostasis and protect neurons. However, certain functional deficits may already be emerging depending on the model system and disease context.

Intermediate Stage of AD

With the progression of AD from early to intermediate stages, astrocytes change alongside, undergoing notable morphological and functional changes. In APPswePS1dE9 mice, hypertrophic, non-proliferative astrogliosis has been observed, associated with a chronic plaque environment.⁹¹ APP/PS1 mice and primary astrocytes show nuclear factor kappa B (NF-κB) activation and increased C3 expression, which impair microglial Aβ clearance and promote inflammation⁹² (Table 1). These astrocytes show heightened interactions with synaptic elements and increased phago-lysosomal activity, internalized dystrophic neurites, and accumulated glycogen granules.⁷⁵ At the intermediate stage, astrocytes shift from a neuroprotective to a more reactive state, attempting to clear Aβ through phagocytosis.⁸⁷ One hallmark of this transition is the metabolic reprogramming of astrocytes from glycolysis to oxidative phosphorylation, which coincides with mitochondrial dysfunction. This change reduces lactate availability for neurons and exacerbates oxidative stress by increasing reactive oxygen species (ROS) production.^85,86 Concurrently, creatine kinase (CK) levels, a critical component of the creatine-phosphocreatine energy buffering system, and ATP levels in astrocytes decrease significantly, impairing ATP buffering and further ATP-dependent physiological processes, such as neurotransmitter uptake and synaptic function.⁸⁵

Additionally, glycolytic impairment in astrocytes reduces the synthesis of L-serine, a precursor for D-serine, required for NMDA receptor activation and synaptic plasticity. Lower D-serine levels subsequently impair NMDA receptor signaling, contributing to further synaptic weakening and cognitive deterioration.^86,93 As the disease progresses, glutamate transporter, particularly GLT-1 expression, is significantly reduced, and as a result, glutamate doesn’t clear efficiently from the synaptic cleft, but it builds up in the extracellular space, leading to excitotoxicity and further neural damage.^93,94

At the intermediate stage, the astrocytes’ autophagic response gradually alters, affecting Aβ clearance and leading to the accumulation of toxic proteins,⁹⁵ as well as altered expression of various enzymes and receptors.⁹⁶ When astrocytes are exposed to Aβ and other harmful stimuli, they not only start releasing pro-inflammatory mediators like interleukin-1 beta (IL-1β) and TNF-α, which fuel neuroinflammation in synergy with activated microglia,^78
-82 but also display exaggerated responses to IL-1β, perpetuating a vicious cycle of neuroinflammatory activation.^83,97 Additionally, it is noted that astrocytes lose their efficiency in Aβ degradation, resulting in an increased extracellular plaque burden. This is further exacerbated in astrocytes expressing the APOE ε4 allele, where autophagic dysfunction impairs Aβ handling,^81,91,98,99 and further leads to astrocyte and neuron dysfunction.¹⁰⁰

Moreover, the accumulation of both monomeric and oligomeric forms of Aβ, as the disease progresses, elevates intracellular calcium,¹⁰¹ which consequently initiates downstream neurodegenerative pathways that compromise astrocytic functions essential for neuronal support. As a result, metabolic support and neurotransmitter cycling will be further impaired, contributing to the vicious cycle of synaptic dysfunction and amplifying neuroinflammation.^{83,84,90,100,101} Sustained calcium dysregulation, coupled with chronic Aβ exposure, triggers astrocytic polarization from A2 to A1, marked by activity of GFAP. The prolonged reactive state often exacerbates the pathology of AD,⁸³ manifesting as abnormally pruned synapses by activating the complement cascade, which results in inappropriate synaptic loss and cognitive impairment.^87,102

Astrocytes at this stage also display altered calcium signaling and increased release of pro-inflammatory cytokines. In AppNL-F mice, astrocytic gamma-aminobutyric acid (GABA) release via monoamine oxidase type B (MAO-B) leads to synaptic silencing and impaired information processing.¹⁰³ In APP/PS1 + in vitro studies, reduced synaptic phagocytosis and downregulation of phagocytic receptors (Mertk/Megf10) result in dystrophic synapse accumulation.¹⁰⁴ Glucose transporter 1 (GLUT1) mislocalization in BRI-Aβ42 mice and humans further impairs glucose uptake and brain energy metabolism¹⁰⁵ (Table 1).

These observations collectively indicate that during the intermediate stage, astrocytes shift from protective to more reactive phenotypes, contributing to inflammation, impaired protein clearance, and synaptic dysfunction.

Late Stage of AD

Generally, astrocytes in the late stage of AD may exhibit more reduced volume, fewer processes, or a complete loss of processes. Surprisingly, atrophic astrocytes are often found in brain regions far from amyloid plaques, indicating a decline in their supportive roles within the neuro-environment. This atrophy affects cognitive abilities by disrupting neurotransmitter uptake,¹⁰⁶ especially glutamate, leading to excitotoxicity and damage to neurons.^93,94

Therefore, at the late stage of AD, A1 astrocytes ratio to A2 is increased due to exposure to cytokines (IL-1α, C1q, TNF-α), and they secrete neurotoxins including interferon beta (IFN-β), interferon gamma (IFN-γ), IFN-α, interleukin-12 (IL-12), interleukin-6 (IL-6), IL-10, and IL-1β, and lead to neuronal and oligodendrocyte death.^83,84 A1 astrocytes, in turn, influence microglia through mediators like complement 3 (C3; Table 1), the endogenous protein orosomucoid-2 (ORM2), and plasminogen activator inhibitor type 1 (PAI-1) as a positive feedback loop.^92,107
-110 In the late stage of AD, an elevated level of C3 secretion drives pathological synapse elimination and disease progression.^92,102 Moreover, secretion of VEGF and other permeability-enhancing molecules disrupts the BBB and enables immune cells to infiltrate the neural tissue and accelerate neuroinflammation¹¹¹ via the entrance of neurotoxic substances to the brain, and neurodegeneration.¹¹²

In the severe stage of AD, astrocytes promote a toxic environment for neurons,⁵⁶ characterized by a senescence-associated secretory phenotype (SASP), and release more inflammatory cytokines^113,114 (Table 1). These cells are marked by chronic release of pro-inflammatory markers such as TNF-α, IFN-γ, interleukin-2 (IL-2), IL-6, IL-10, IL-1β, granulocyte-macrophage colony-stimulating factor (GM-CSF), chemokine C-X-C motif ligand 1 (CXCL1), matrix metalloproteinase 3 and 10 (MMP-3 and MMP-10), and tissue inhibitor of metalloproteinases 2 (TIMP-2),¹¹⁵ and their functional capacity becomes significantly compromised, leading to impaired metabolic support for neurons.⁸⁵ APP-PS1 mice and human post-mortem brain samples report increased lysosomes, lipid bodies, and “dark” astrocytes, creating peri-synaptic and perivascular stress environments.⁷⁵ Other mechanisms of late-stage astrocyte toxicity include impaired glycolytic flux and L-serine/D-serine metabolism,⁸⁶ and overactivation of purinergic receptors¹¹⁶ (Table 1).

Overall, the transition from A2 to A1 astrocytes reflects the dynamic changes in astrocytic function throughout the progression of AD.⁵¹ The balance between these subtypes can significantly influence the disease’s trajectory, with A1 astrocytes contributing to neurotoxicity and A2 astrocytes providing neuroprotection, especially in the early stages.⁵⁸

Mechanisms Underlying Astrocytes’ Dual Role in the Healthy Brain and the Brain With AD

As we mentioned above, astrocytes can exhibit both harmful and protective roles based on intrinsic and extrinsic factors.^50,60 At the early stage of AD, astrocyte-derived exosomes have been demonstrated to contain neuroprotective factors, such as BDNF, which support neuronal survival and restore memory and improve synaptic properties in AD models.¹¹⁷

In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) is expressed in astrocytes following Aβ exposure, protecting against oxidative stress.⁸³ Another molecule released from activated astrocytes is tissue inhibitor of metalloproteinase-1 (TIMP-1), with neuroprotective properties in early exposure to Aβ. TIMP-1 promotes neuronal survival and ameliorates cognitive deficits in Aβ-infused rodent models.¹¹⁸

Yes-associated protein (YAP) is another essential factor downregulated in hippocampal astrocytes in AD. YAP causes premature senescence, characterized by decreased cell proliferation, hypertrophy, increased senescence-associated β-galactosidase activity, and increased expression of senescence-related genes like NF-κB, p16, and p53. YAP also helps prevent astrocytic senescence by regulating cyclin-dependent kinase 6 (CDK6). These indicate that the YAP-CDK6 pathway plays a crucial role in maintaining astrocyte health and function in AD, suggesting that enhancing YAP activity is a possible therapeutic strategy for mitigating cognitive decline in AD.⁹⁶

As the AD progresses, reactive astrocytes shift from a supporting role to an inflammatory role through various mechanisms.^119,120 Exposure to neurotoxic stimuli (such as Aβ plaques) causes astrocytes to become more reactive,¹⁰³ while, on the other hand, Aβ accumulation disrupts astrocytic function, resulting in a breakdown of the BBB, and the entrance of neurotoxic substances into the brain,¹¹² together with disruption of glucose transporter 1 (GLUT1) localization, and thereby energy deficits, and neuronal damage.¹⁰⁴ Besides, Aβ significantly increases calcium via nuclear factor of activated T-cells (NFAT),¹⁰¹ also leads to astrocytic metabolic disturbance, and further neurodegeneration.⁹⁰

In addition, astrocytes exhibit mitochondrial dysfunction in AD by changing their energy metabolism and reducing CK and ATP in cells. Loss of CK function in astrocytes also increases oxidative stress and worsens neuronal injury.⁸⁵ Then, dysfunctional astrocytes exhibit impaired glycolytic flux, which reduces L-serine production, a vital component for synaptic plasticity. Low levels of D-serine, derived from L-serine, can impair NMDA receptor function, further contributing to synaptic deficits and cognitive decline.^86,93 All together, these events cause the elevation and penetration of neurotoxins to the CNS, contributing to neurodegeneration,¹¹¹ neuroinflammation, and cognitive dysfunction.^121
-123

Therefore, in parallel with the progression of disease, particularly at the late stage of AD, astrocyte activity leads to toxicity and neurodegeneration^124,125 via elevation in ROS, oxidative stress,^126,127 neural damage,⁷⁸ and disturbance of the BBB integrity.

Meanwhile, further contribution of microglia with astrocytes exacerbates AD pathology by impairing autophagic function⁹⁹ and reducing the clearance of Aβ plaques.^81,91 Because, physiologically, these cells internalize and degrade Aβ through low-density lipoprotein receptor-related proteins (LRP1 and LRP4), α7 nicotinic acetylcholine receptors (α7nAChR), and scavenger receptors (SCARB1).¹⁰⁴

In addition to the close relationship between Aβ and astrocytes, these cells are capable of internalizing and degrading tau protein.⁸⁸ Buildup of tau in astrocytes has been tied to changes in mitochondrial dynamics and function, which can reduce neurogenesis and impair the overall neuronal network.⁸⁹ Finally, buildup of toxic proteins,⁹⁸ and impaired neuronal communication¹⁰³ promotes synaptic depression and impaired memory retention,⁴⁶ and forgetting.

As AD progresses to more neuroinflammation and neurodegeneration, astrocytes spread neuroinflammation through activation of the NF-κB pathway.¹²⁸ Additionally, NF-κB activation in astrocytes correlates with enhanced expression of complement factors, which further modulate the inflammatory response and influence amyloid pathology.⁸⁴ Moreover, other mediators, such as the Platelet-activating factor receptor (PTAFR), also operate through NF-κB, leading to neuroinflammation and cognitive deficits in the later stages of AD.

Moreover, astrocytes engulf synapses via the classical complement pathway (CCP), especially in a C1q-dependent manner, and the overactivation of this pathway results in excessive synaptic loss and cognitive decline.¹²⁹

Another molecular target regarding astrocytes’ roles in AD might be phosphoprotein enriched in astrocytes 15 (PEA15). PEA15 is positively associated with the astrocytic capacity for Aβ clearance through phagocytosis, highlighting the potential therapeutic implications of this pathway in the late stages of AD.¹³⁰

Last, but not least, purinergic signaling influences neuroinflammation and astrocytic function. Silencing purinergic receptor P2Y1 (P2Y1R) decreases the production of cytokines such as IL-1β and IL-6, mitigates cognitive decline, and improves BBB integrity, offering a potential gene therapy strategy for AD.¹¹⁶

Therapeutic Strategies Considering Astrocytic Activation Throughout the Progression of Alzheimer’s Disease

As we discussed above, astrocytes adopt a more homeostatic or even protective phenotype, whereas in mid-to-late stages, there is a shift toward pro-inflammatory, neurotoxic “reactive” astrocytes. Consequently, alternative therapeutic approaches such as anti-inflammatory small molecules, receptor agonists, or modulators of signaling pathways also have the potential to regulate astrocytic activation and influence neuroinflammatory response. For example, targeting astrocytic metabolism or increasing glymphatic clearance may enable astrocytes to restore their protective function, specifically in the early stages of disease progression, thus inhibiting disease progression. Therefore, agents targeting lactate shuttling or mitochondrial dysfunction, such as indoleamine-2,3-dioxygenase 1 (IDO1) blockers, demonstrate the importance of astrocyte-neuron metabolic coupling, especially in prodromal and early symptomatic phases, and rescued cognition in mouse models of both amyloid and tau pathology.^131
-133

In addition, therapeutic modulation of lysosomal function may restore “healthier” astrocyte phenotypes, reduce inflammation, and improve clearance of pathological proteins. In this era, Artemisinin, an anti-malarial drug, has been shown to suppress astrocytic overactivation in AD models via the NF-κB axis.^134
-136 Other small molecules (eg, isothiocyanates) can inhibit NF-κB signaling in astrocytes, reducing inflammatory cytokine production, oxidative stress, and potentially tau pathology.^137
-139 Anti-Aβ immunotherapies may indirectly reduce astrocytic reactivity by lowering plaque burden. Small-molecule modulators of inflammatory signaling (eg, NF-κB, JAK/STAT3, NLRP3 inhibitors) show promise in shifting astrocytes away from pro-inflammatory phenotypes, in a stage-dependent manner; early intervention tends to preserve synaptic integrity, whereas late intervention may be insufficient once downstream neurodegeneration is established.

Another reagent, MFG-E8, prevents synaptic loss very early in disease by preventing A1 inflammatory phenotypes. Therefore, if the clinical goal is to intervene before irreversible synapse/neuron loss, the highest-priority directions should be considered at an early stage. Modulating astrocyte activation carries the risk of suppressing helpful/homeostatic astrocyte functions if applied too broadly or at the wrong stage. Preclinical studies indicate that, in late-stage Alzheimer’s disease, some inhibitors, such as Venlafaxine and Fluoxetine, targeting inflammatory astrocytes aim to reduce neuroinflammation and astrocyte overactivation. These antidepressants have been associated with reduced inflammatory signaling in astrocytes by inhibition of JNK1 and STAT3 pathways, thereby lowering pro-inflammatory cytokines such as IL-6 and IL-1β and promoting an anti-inflammatory state.¹⁴⁰ On the other hand, activation of Nrf2 in astrocytes is also promising, as it increases antioxidant responses and suppresses pro-inflammatory transcription, helping maintain more homeostatic astrocyte states.^141
-143 For example, administration of natural compounds such as curcumin,^144,145 genistein,¹⁴⁶ resveratrol,^147,148 and other antioxidative phytochemicals has been shown to attenuate astrocyte-mediated neuroinflammation and improve cognitive function in late-stage AD models, and to support neuroprotection in the AD brain by suppressing NF-κB signaling, a master regulator of inflammation.

In summary, astrocytes can exhibit both neuroprotective and neurotoxic effects, depending on the disease context, so any potential treatment will likely need to be stage-specific to be effective. The stage-dependent nature of astrocytic activation indicates that the timing of therapy is critical in achieving desired effects. The most beneficial interventions may also involve promoting homeostatic astrocyte effects in prodromal or early AD. In contrast, anti-inflammatory or reactivity-suppressing therapies may be more beneficial in later stages when reactive gliosis is more prominent. Besides, using biomarkers such as glial fibrillary acidic protein (GFAP) in plasma or CSF may help track astrocyte reactivity in patients and guide therapeutic decisions. Indeed, plasma GFAP is elevated even in early amyloid pathology and may reflect astrocytic activation waves. Besides, personalized therapeutic strategies may be developed by integrating neuroinflammatory biomarkers (eg, cytokines, GFAP) with clinical staging to decide which patients will benefit most from astrocyte-targeted therapies.

Summary

We reviewed the complex classification of astrocyte subtypes and their responses across AD progression and found that astrocytes exhibit substantial morphological and functional plasticity, depending on the AD stage. This adaptability results in a spectrum of phenotypes, including A1, A2, and other intermediate states, which poses a challenge for the development of therapies that selectively target astrocytic subpopulations.

A2 astrocytes appear in the early stages of AD, exhibit mild reactive astrogliosis without proliferative scar formation, and protect against neurodegeneration by clearing Aβ via endocytosis and secreting anti-inflammatory cytokines and neurotrophic factors.

At the intermediate stage, astrocytes undergo a shift from a neuroprotective to a more reactive state. Their metabolism shifts from glycolysis to oxidative phosphorylation, which coincides with mitochondrial dysfunction, ATP imbalance, and impairment in neurotransmitter uptake and synaptic function. Additionally, astrocytes lose their efficiency in Aβ degradation, resulting in an increased extracellular plaque burden. Sustained calcium dysregulation, coupled with chronic Aβ exposure, triggers astrocytic polarization from A2 to A1, marked by activity of GFAP, and reduced volume.

At the late stage of AD, the A1 astrocyte ratio to A2 is increased due to exposure to inflammatory cytokines, leading to neuronal and oligodendrocyte death, synapse elimination, and disease progression.

Overall, the transition from A2 to A1 astrocytes reflects the dynamic changes in astrocytic function throughout the progression of AD. The balance between these subtypes can significantly influence the disease’s trajectory, with A1 astrocytes contributing to neurotoxicity and A2 astrocytes providing neuroprotection, especially in the early stages.

This review suggests that it is crucial to consider the stage of the disease when designing successful therapeutic strategies targeting A1 inflammatory astrocytes, as this may risk unintended consequences.

Footnotes

Acknowledgements

We appreciate the authors of the original articles who provided the data described in this review article.

ORCID iDs

Helya Bolouki Azari

Parvin Babaei

Mobina Taghva Nakhjiri

Author Contributions

HBA investigation, project administration, resources, visualization, writing—original draft, writing—review and editing. PB conceptualization, methodology, resources, supervision, validation, writing—review and editing. MTN investigation, writing—original draft, writing—review and editing. All authors read and approved the final manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Transparency Declaration

This manuscript is an honest, accurate, and transparent account of the reported study. No important aspects of the study have been omitted, and any discrepancies from the planned research have been explained.

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Stage-Dependent Function of Astrocytes in Alzheimer’s Disease: A Review

Abstract

Keywords

Introduction

Methods

Astrocytes Function in the Healthy Brain

Astrocyte Phenotypes in Alzheimer’s Disease

A1 Astrocytes

A2 Astrocytes

Polarization of A1 to A2 Astrocytes in the Stages of AD

Early Stage of AD

Intermediate Stage of AD

Late Stage of AD

Mechanisms Underlying Astrocytes’ Dual Role in the Healthy Brain and the Brain With AD

Therapeutic Strategies Considering Astrocytic Activation Throughout the Progression of Alzheimer’s Disease

Summary

Footnotes

Acknowledgements

ORCID iDs

Author Contributions

Funding

Declaration of Conflicting Interests

Transparency Declaration

References