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Review

Astrocytes in selective vulnerability to

neurodegenerative disease
Till S. Zimmer, 1,2 Adam L. Orr, 1,2,3 and Anna G. Orr 1,2,3,
*

Selective vulnerability of specific brain regions and cell populations is a hallmark Highlights
of neurodegenerative disorders. Mechanisms of selective vulnerability involve Selective vulnerability in neurode-
neuronal heterogeneity, functional specializations, and differential sensitivities generative disorders affects specific
neuronal populations and may involve
to stressors and pathogenic factors. In this review we discuss the growing body
non-neuronal cells, such as astrocytes,
of literature suggesting that, like neurons, astrocytes are heterogeneous and spe- which have multifaceted roles in brain
cialized, respond to and integrate diverse inputs, and induce selective effects on function.
brain function. In disease, astrocytes undergo specific, context-dependent
Astrocytes are phenotypically and func-
changes that promote different pathogenic trajectories and functional outcomes. tionally heterogeneous and responsive
We propose that astrocytes contribute to selective vulnerability through maladap- to diverse signals as a function of age,
tive transitions to context-divergent phenotypes that impair specific brain regions brain region, environmental conditions,
and functions. Further studies on the multifaceted roles of astrocytes in disease and other variables.

may provide new therapeutic approaches to enhance resilience against neurode- Astrocytic responses and contributions
generative disorders. to neural impairments and pathogenic
processes in neurodegenerative condi-
tions are emerging as selective and
context-dependent.
Selective vulnerability is a common feature of neurodegenerative disorders
Neurodegenerative disorders are age-related neurological illnesses that cause progressive Astrocytes may promote selective
decline in behavioral, cognitive, social, and emotional processes. Examples of these disorders vulnerability in neurodegenerative dis-
orders by inducing distinct effects
include Alzheimer’s disease (AD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis across different contexts.
(ALS), Huntington’s disease (HD), and Parkinson’s disease (PD). Neurodegenerative disorders
are characterized by proteinopathy, brain atrophy, neuronal dysfunction and cell death, glial
alterations, neuroimmune responses, and neurovascular changes. The underlying neuropathogenic
molecular pathways are complex and include impairments in proteostasis, RNA processing, gene
expression, metabolic pathways, and intracellular signaling mechanisms [1].

A central feature of all neurodegenerative disorders is the vulnerability of select neuronal populations
and brain regions to progressive dysfunction and pathology, whereas other regions and cell popu-
lations are largely spared pathology or exhibit functional resilience despite the presence of pathology.
In AD, impairments typically begin in pyramidal neurons of the entorhinal cortex and hippocampal
CA1 region, as well as in noradrenergic neurons in the locus coeruleus and regions of the neocortex
1
[2]. In FTD, van Economo neurons and fork cells within the frontoinsular cortex and anterior cingulate Appel Alzheimer’s Disease Research
Institute, Weill Cornell Medicine, New
cortex are more susceptible [3], whereas in ALS spinal cord motor neurons are lost early [4]. In
York, NY, USA
HD, striatal medium spiny GABAergic neurons degenerate [5], whereas PD involves the loss of 2
Feil Family Brain and Mind Research
dopaminergic neurons of the substantia nigra [6]. As these disorders progress, secondary neuronal Institute, Weill Cornell Medicine, New
York, NY, USA
vulnerability, spread of proteinopathy, and various neuropathological cascades continue to spread 3
Neuroscience Graduate Program, Weill
selectively across specific brain regions and neuronal populations. Cornell Medicine, New York, NY, USA

In addition to regional differences, there are also differences in impairments and degeneration
across affected individuals with similar diagnoses and genetic risk factors. Why particular neural
cell populations, brain regions, and individuals are more susceptible to degenerative processes *Correspondence:
and functional decline while others are resilient remains enigmatic. Identifying the processes [email protected] (A.G. Orr).

Trends in Neurosciences, April 2024, Vol. 47, No. 4 https://doi.org/10.1016/j.tins.2024.02.008 289

© 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
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underlying selective vulnerability is likely crucial for pinpointing early pathogenic mechanisms and
advancing the development of novel prognostic biomarkers, preventative strategies, and thera-
peutics to halt disease onset and progression.

Although neuronal pathology is a primary hallmark of neurodegenerative diseases, non-neuronal

cells of the brain are also affected and play key roles in pathogenesis. Among these cells, astro-
cytes are a prevalent type of glial cell that enables and regulates neural function and may contribute
to pathogenic cascades in disease. Astrocytes are increasingly recognized for their heterogeneity
and functional specializations, suggesting that differential astrocytic responses in disease may
represent a crucial aspect of selective vulnerability. Given that astrocytes are essential for proper
brain function, we posit that exploring astrocytic roles in vulnerability may be paramount to under-
standing and treating neurodegenerative disorders.

In this review we discuss recent evidence implicating astrocytes in selective vulnerability associated
with neurodegenerative disorders. We first highlight key disease-related mechanisms and the
involvement of non-neuronal cells, and then review the fundamental roles of astrocytes as integra-
tors of diverse cues and dynamic modulators of brain function. Focusing on recent studies in
the context of neurodegenerative disorders and their mechanisms, we describe converging
evidence that astrocytes have context-specific changes and roles in disease that may promote
selective vulnerability. These discoveries have important implications for the understanding of
astrocyte pathobiology and therapeutic development for neurodegenerative disorders.

Selective vulnerability is multifactorial and involves neuronal, glial, and

neurovascular elements
Selective vulnerability of brain regions or neuronal populations is likely a result of multiple converging
pathways and variables. In part, it involves cell-autonomous differences in neuronal physiology
and pathogenic processes [7,8], including divergence in proteostasis, gene expression, excitability,
and cell stress mechanisms. A key signature of neurodegenerative disorders is progressive
proteinopathy, which is the accumulation, mislocalization, aggregation, and spread of aberrant
proteins – including amyloid-β (Aβ), tau, TDP-43, and α-synuclein – in specific neural cell pop-
ulations and brain regions. Proteostasis, a process that regulates protein expression, folding,
trafficking, degradation, and clearance [9,10], is affected in neurodegenerative disorders,
and its malfunction likely promotes selective neuronal degeneration and related disease cas-
cades [11–14]. Of note, Aβ, tau, and other proteins have the propensity to form different types
of pathological aggregates and strains that may result in distinct neuropathological sequelae
among individuals [15,16]. Although the extent of proteinopathy in patients does not always corre-
late with clinical decline, likely for complex biological reasons, the accumulation and spread of
proteinopathy is generally associated with progressive neural impairments and disease severity,
and has been causally linked to functional impairments in diverse model systems. Additionally, in-
dividuals carrying specific genetic variants that promote or prevent proteinopathy often have in-
creased or reduced odds of developing neurodegeneration, respectively [1,17]

Specific brain regions and neuronal circuits may be more vulnerable to disease as a function of
their neurotransmitter systems, ion buffering capacity, and other intrinsic factors, which can
cause distinct stress-related responses culminating in excitotoxicity, synapse loss, and cell
death [18–21]. Neurons also depend on efficient energy generation, and recent studies in
mouse models and human neural cells point to mitochondrial dysfunction and changes in neuro-
nal metabolism in degeneration of select neuronal populations [22–24]. Notably, aging is a strong
risk factor for neurodegenerative disorders and modulates many of the mechanisms underlying
neuronal vulnerability to disease [25,26].

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In addition to cell-autonomous neuronal mechanisms, recent work emphasizes glial and

neurovascular changes as contributors to disease. Concurrent pathological processes – including
neuroinflammation, blood–brain barrier (BBB) and neurovascular dysfunctions, white matter
changes, and alterations in brain metabolism – are prominent and implicate non-neuronal
cell types in neurodegenerative disorders [1,27]. Many genetic risk factors and proteins linked to
disease are enriched in non-neuronal cells or affect their functions [28]. Neurovascular impairments
are hypothesized to precede functional impairments, and cerebral oxygenation, nutrient transport,
and removal of neurotoxic factors are crucial to brain homeostasis [29,30]. In addition, microglial
responses and white matter alterations are closely linked to aging and neurodegenerative disease
[31–33]. Microglial and oligodendrocyte interactions with neurons and astrocytes impart additional
layers of complexity to disease mechanisms. Consequently, a multifactorial and nonlinear patho-
genic process occurs in neurodegenerative conditions characterized by neuronal and non-
neuronal alterations and bidirectional cell–cell interactions among different cell types [34–36]
(Figure 1).

Many of these disease-associated non-neuronal changes, including astrocyte alterations [37],

can precede the onset of apparent clinical symptoms by many years, suggesting that robust
compensatory mechanisms are engaged to preserve brain function and promote resilience.
These protective mechanisms can also be selective to specific brain regions and cell popula-
tions [38], and may further promote variability in disease onset or progression. Therefore, the
pathogenesis of neurodegenerative disorders is complex and dynamic, and depends not
only on intrinsic neuronal mechanisms but also on glial, neuroimmune, and neurovascular
changes and the interplay of pathogenic and protective cascades in these different systems.
Moreover, individual lifestyle variables such as diet and physical activity can also affect disease
vulnerability [39,40].

In this broader view of disease pathogenesis, astrocytes occupy a crucial niche at the interface of
neurons, other glial cells, the vasculature, and infiltrating immune cells and peripheral factors
[41,42]. Historically, astrocytes have been viewed as largely homogeneous support cells with
similar functions and responses to disease. However, emerging evidence is revealing a rich diver-
sity of astrocytic features and functions within and across brain regions (Figure 2), which is likely
due to their developmental lineage, positional identity, and sensitivity to various local inputs
and cues in their microenvironment [43]. Considering their multifunctional roles in neurovascular

Contributing variables Multicellular interactions Diverse molecular changes Nonlinear and selective pathogenesis

Proteinopathy
Synaptic
impairments Subpopulation A
Age Genetics DNA and RNA
Neurovascular Astrocytic-neuronal dysregulation
Pathogenesis

dynamics dynamics Aberrant signaling

pathways
Abnormal Subpopulation B
neuronal activity
Lifestyle Sex Neuroimmune
cascades
Altered
mitochondrial Metabolic Subpopulation C
Astrocytic-microglial Astrocytic-myelin processes dysregulation
Brain region Neural circuit dynamics dynamics
Time

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Figure 1. Vulnerability to neurodegenerative disorders is multifactorial. Multiple intrinsic variables affect the onset and progression of neurodegenerative disease,
including age and genetics, but also environmental and lifestyle factors. These and other variables influence the complex multicellular interactions between different cell
types in the brain and their functions. Dynamic molecular changes, detrimental and protective, occur within multiple cell types and affect cell–cell interactions,
contributing to disease complexity. Together, these changes result in nonlinear pathogenesis and selective vulnerability within specific subpopulations of cells, brain
regions, and individuals. Figure created with BioRender.

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Molecular Structural Functional Figure 2. Molecular, structural, and

diversity diversity diversity
functional diversity in astrocytes.
Astrocyte diversity involves cell-
P
autonomous molecular features,
structural and positional identity of
astrocytes throughout the brain, and the
Gene regulation Brain region Neurovasculature integration of astrocyte populations into
CH2OH
their functional contexts. All three aspects
OH
O
of heterogeneity are interconnected,
OH OH
OH

ATP
ROS and facilitate precise, dynamic, and
multifaceted responses by astrocytes to
Metabolome Metabolism various physiological and pathological
signals. Ultimately, astrocytic responses
have direct and indirect effects on
neuronal function and survival, and
thereby have major roles in the
Surface proteins Local connectivity Neuronal modulation pathogenesis of neurodegenerative
diseases. Abbreviations: ATP, adenosine
triphosphate; ROS, reactive oxygen
species. Figure created with BioRender.

Signaling pathways Subcompartments Neuroimmune response

Secretome Remodeling Cellular environment

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dynamics, brain metabolism, neuronal activities, neural stress responses, and neuroimmune cas-
cades, astrocytes are well positioned to affect many of the mechanisms linked to selective
vulnerability or resilience to disease. In the following section, we briefly summarize recent evi-
dence indicating that astrocytes have extensive functional heterogeneity, and respond to stimuli
in a versatile and context-dependent manner. Thereafter, we discuss the potential involvement of
astrocytes in selective pathogenesis linked to neurodegenerative disorders.

Astrocytes integrate numerous cues and have diverse features and functions
Astrocytes are prevalent glial cells that tile the brain and are estimated to contact hundreds of
thousands of synapses and interact with microglia, oligodendrocytes, and neurovascular ele-
ments [44]. Astrocytes are involved in a wide range of normal and pathogenic processes [45]
through diverse arrays of receptors, channels, adhesion molecules, and other surface factors
that sense neurotransmitters, cytokines, growth factors, and other types of molecules pro-
duced by surrounding cells, afferent synaptic inputs, and the periphery [46,47]. In response
to these various cues, astrocytes regulate synaptic and neural circuit functions, other glial
cells, vascular elements, and homeostatic processes. Historically, astrocytes were frequently
studied in isolation or in the context of injury or disease, which can alter their phenotype and
function. In addition, long-enduring dogmas asserting that astrocytes are nonexcitable and
slow to respond have perpetuated a notion that they are unable to effectively detect, store,
and transmit behaviorally relevant neural information. These challenges, together with the slow de-
velopment of tools to precisely target and manipulate astrocytes in vivo, have delayed our under-
standing of astrocyte biology. However, recent studies using more advanced methods suggest
that astrocytes are crucial integrators and conductors of brain function, including behavior, in
part due to their intimate associations with neurons and other cell types and their precise effects
on neural function.

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Astrocytes, like neurons, are heterogeneous and have region-specific morphological and molecular
signatures, as well as region- and context-specific calcium dynamics and neurotransmitter release
properties [48–50]. Astrocytes regulate diverse neuronal functions, such as basal synaptic strength
in hippocampal CA1 neurons, inhibition in cortical circuits related to goal-directed behaviors, and
modulation of sensory transmission in arousal and sleep [51–53], as established primarily in rodent
models. Astrocytes exhibit distinct functional properties involving fast and slow signaling mecha-
nisms [53,54], and modulate neural network excitation and synchronization required for sensory
information processing, storage, and behavioral output [55,56]. Indeed, in mouse models, astrocytic
signaling has been shown to regulate cognitive function and behavior [57,58], including learning and
memory-linked processes [59–61]. Aberrant changes in the activation of astrocytic G-protein-
coupled signaling can lead to neural hyperactivity and specific behavioral deficits [59,62–64]. Studies
are also revealing astrocytic contributions to social and emotion-related behaviors and neuro-
psychiatric conditions, as recently reviewed [65].

Evidence in rodent and ferret models suggests that astrocyte engagement in neural circuit activities
is selective, dynamic, and dependent on context. Astrocytes in the striatum can discriminate and
differentially regulate neuronal activities in specific circuits despite being physically intermingled
with multiple circuits [66], and these astrocytes lack evoked calcium-based responses to neocor-
tical inputs, but gain aberrant evoked responsiveness in the context of HD-related pathology [67].
Somewhat similarly, astrocytes in the neocortex discriminate between cholinergic inputs from
neuronal populations in the nucleus basalis activated by visual stimuli [68], tune their responses
to distinct features of visual stimuli [69], and shift their responsiveness and calcium signaling
patterns based on the sleep–wake cycle and levels of norepinephrine [49,53,70,71]. In addition,
astrocytes in the CA1 region of the hippocampus can selectively modulate CA1 neurons projecting
to the anterior cingulate cortex but not those projecting to the nucleus accumbens, thereby
modulating remote memory [62]. Moreover, CA1 astrocytes participate in frequency-specific
dendritic integration [72]. Thus, in contrast to previous views that astrocytes are functionally homo-
geneous, emerging studies reveal a high degree of context-dependent functional precision and
adaptation in astrocytic–neuronal interactions across a range of circuits and domains [73].

Developmental patterning affects astrocyte maturation and contributes to early heterogeneity in

astrocytes across different brain regions. Local neuronal cues also play important roles in defining
astrocytic phenotypes, including their gene expression and functional features such as specific
metabolic fluxes and transporter currents [74–76]. Notably, neuronal cues may continually refine
astrocytic properties and promote distinct transcriptional, morphological, and functional features
[77,78]. Astrocytic properties are also heterogeneous within brain regions, namely within neocor-
tical layers [79,80] and hippocampal subregions, including distinct areas of the dentate gyrus
[50,81,82]. Astrocyte heterogeneity is postulated to subserve specific neural processes and
requirements in the local neural environment. There are also structural and molecular differences
within subcellular compartments of individual astrocytes, which have distinct and potentially
specialized proteomic signatures [83], intracellular calcium dynamics [84], and mitochondrial distri-
butions [85], revealing a high degree of organizational sophistication and complexity at the subcel-
lular level (Figure 2).

Astrocytic alterations and contributions to pathogenic processes are selective

and context-dependent
Astrocytes have been implicated in diverse neurological and neuropsychiatric conditions, including
most neurodegenerative disorders. Various perturbations in the brain can induce reactive astrocyte
phenotypes, which are broadly characterized as changes in astrocytic morphological, molecular,
and functional features in response to pathological or stress-associated conditions. Although

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general markers of astrocyte reactivity, such as increased glial fibrillary acidic protein (GFAP)
expression, have historically served as indicators of astrocytic alterations, the use of binary charac-
terization (e.g., normal or reactive) is now recognized as insufficient and potentially misleading due
to the diversity of astrocytic changes and their influence across different contexts [86,87]. For
example, in mouse models, astrocytes in the spinal cord and striatum adopt diverse and dynamic
reactive states across different pathological contexts through changes in the activities of multiple
transcriptional regulators, as assessed by chromatin accessibility measures, RNA sequencing,
and gene perturbation [88,89].

Aging and neuroinflammation are major risk factors for neurodegenerative disorders and facilitate
disease onset and progression [25,90]. The effects of aging and immune responses on glial cell
phenotypes are brain-region-specific and appear to be pronounced in the white matter [32,91].
Aging induces divergent transcriptional profiles in astrocytes within different brain regions and is
associated with diminished astrocyte-mediated synaptic plasticity in mice and humans [92–94].
It has not been firmly established, however, whether certain aging-induced astrocytic changes in
specific brain areas promote regional vulnerability or resilience to dementia-linked pathology, and
if so, how. In animal models, astrocytes also have regional and time-dependent responses in
lipopolysaccharide (LPS)-induced neuroinflammation, which induces distinct subpopulations of
astrocytes with differing transcriptional profiles [95,96]. Therefore, spatiotemporal differences in
astrocytic phenotypes consequent to aging and inflammation may contribute to differential brain
vulnerability to disease, possibly synergizing with specific neuronal alterations in susceptible
regions and giving rise to selective and localized neurodegenerative cascades. In the following
we highlight further evidence that astrocytes are differentially affected by dementia-associated
factors and pathological processes, and in turn influence neuronal functions and pathogenic trajec-
tories in a selective and context-dependent manner (Figure 3).

Proteinopathy
Astrocytes can differentially modulate proteinopathy and its effects on brain function. The uptake
and clearance of protein aggregates by astrocytes can become progressively impaired in patho-
logical conditions [97]. Astrocytes take up protein aggregates to either degrade them intracellu-
larly or deliver them to waste removal systems, although alternative pathways might also exist.
Brain clearance of protein aggregates depends in part on bulk flow through perivascular spaces
[98], and water movement through astrocytic aquaporin 4 (AQP4) channels is hypothesized to
facilitate Aβ removal [99–101]. Notably, AQP4 levels are reduced in astrocytic endfeet in mouse
models of AD pathology and in individuals with AD or cerebral amyloid angiopathy [102,159],
which is characterized by aberrant Aβ accumulation in perivascular spaces. Reductions in clear-
ance are associated with increased Aβ load in humans [103], implicating changes in astrocytic
clearance mechanisms in AD pathogenesis. AQP4 levels differ among astrocyte subpopulations
and subcompartments, with AQP4 enrichment in astrocytic endfeet [104,105]. Differences in AQP4
function may promote local variations in Aβ clearance and affect the capacity of brain regions to
cope with protein accumulation, thereby correlating with pathogenesis and neurocognitive changes.
In contrast to AQP4 reductions in AD, AQP4 levels are enhanced in FTD linked to progranulin
mutations [106], highlighting potential disease-specific changes in clearance mechanisms.

In addition to potential differences in BBB-dependent clearance, astrocyte subpopulations in

human organoids and mouse models have differential expression of phagocytosis and autophagy
factors with aging and disease [107–109]. Reduced autophagy in human and mouse astrocytes
may be a driver of astrocytic impairments and consequent neuronal damage, especially in those
with genetic risk factors for neurodegeneration [110]. Considering that astrocytes serve as gate-
keepers positioned between brain parenchyma and glymphatic waste removal, reduced

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(A) Differential protein clearance Physiology Pathology (B) Differential metabolic load Physiology Pathology

Cortex Tau
Cortex
10mV
50ms

Aβ
α-syn Resilient
AQP4 Hyperexcitability
Other
Low metabolic load

Basal regions Hippocampus

10mV
50ms

Vulnerable
Hyperexcitability

Protein removal Protein buildup High metabolic load

(C) Differential neurotransmission effects FTD Injury (D) Differential synapse maintenance HD
Impaired
GPCRs
10mV
50ms
10mV
mV
V
50
0ms
10m
mV
mV
50
50
0ms synapse growth
α β/γ Altered
Glutamate GABA Striatum Gi/o signaling
Thalamus
Gene
1 0m V
10mV
expression
50ms
50m
5 0m
0 m

Synaptic loss Hyperexcitability

AD / FTD AD Aging
Aβ Impaired pruning
and growth
TDP-43
Chemokines Hippocampus
Hippocampus GABA Reduced phagocytosis
and synaptogenic factors
Disrupted
Presynaptic changes Tonic inhibition proteosomes
Aberrant excitation and lysosomes

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Figure 3. Astrocytes may contribute to selective vulnerability in disease through divergent, context-dependent phenotypes that affect specific brain
regions and functions. (A) Aberrant proteins implicated in disease are cleared from the brain through various mechanisms, including aquaporin-4 (AQP4)-dependent
protein removal. Astrocytes in basal brain regions may have a higher clearance burden and, in conjunction with changes in AQP4 localization and expression, might
promote selective vulnerability in the basal regions. (B) Cortical astrocytes contact more blood vessels and fewer synapses per cell than hippocampal astrocytes. The
resulting higher metabolic load carried by hippocampal astrocytes may predispose hippocampal synapses and other neural elements to metabolic vulnerability and the
detrimental effects of neural hyperexcitability. (C) Astrocytes regulate neurotransmission in a state-dependent and region-specific manner. In frontotemporal dementia
(FTD), thalamic astrocytes may remove less glutamate via surface transporters and promote synaptic loss and, in brain injury, remove less GABA and induce
hyperexcitability. Aberrant TDP-43 accumulation in hippocampal astrocytes promotes region-specific expression of chemokines that induce presynaptic changes and
aberrant excitatory transmission. Hippocampal astrocytes in Alzheimer’s disease (AD) overproduce GABA and impair neuronal function through increases in tonic
inhibition. (D) Astrocytes can differentially modulate synaptic formation and loss. Striatal astrocytes in the context of Huntington’s disease (HD)-related pathology have
altered Gi/o-coupled signaling leading to gene expression changes that impair synaptogenesis. In aging, subpopulations of hippocampal astrocytes have disrupted
proteosomes and lysosomes, which impairs synaptic pruning and secretion of synaptogenic factors. Abbreviations: α-syn, α-synuclein; Aβ, amyloid-β; Gi/o, Gi/o-coupled
receptor signaling; GPCRs, G-protein-coupled receptors; TDP-43, transactive response DNA-binding protein of 43 kDa. Figure created with BioRender.

phagocytic and AQP4-dependent clearance mechanisms may synergize to hasten the accumula-
tion and aggregation of aberrant proteins. Most cerebrospinal fluid (CSF) is hypothesized to drain at
the base of the brain via lymphatic vessels running in parallel to cranial nerves [111]. Accordingly,
despite generally similar levels of astrocytic AQP4 throughout the brain, there is likely a high local
burden on astrocytic clearance mechanisms in basal brain regions. Interestingly, these regions
are also among the earliest to display signs of Aβ, tau, and α-synuclein accumulation in humans,
including basal brain regions and midbrain, suggesting that astrocytes in those regions could be
affected by aging and other risk factors and promote regional vulnerability to altered proteostasis
and onset of pathogenic cascades that subsequently spread to other brain areas.

In addition to extracellular clearance defects, intracellular protein dysregulation in astrocytes is

sufficient to cause progressive neuronal impairments and behavioral decline. Pioneering studies
in the context of familial ALS suggest that astrocytic protein aggregates in transgenic superoxide
dismutase 1 (SOD1) mouse models promote neurodegeneration by disturbing glutamate

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homeostasis, and that genetic deletion of mutant SOD1 selectively in mouse astrocytes slows
disease progression [112]. Moreover, in mouse models involving targeted viral vector manipula-
tions, tau accumulation in hilar astrocytes of the hippocampus was sufficient to cause bioener-
getic failure, reductions in neurogenesis, and selective impairments in inhibitory neurons [113].
Similarly, TDP-43 accumulation induced in hippocampal astrocytes of adult mice causes
progressive memory loss through alterations in astrocytic antiviral pathways and selective impair-
ments in presynaptic function [114]. Of note, learning, motor function, and innate behaviors in
mice were not affected by astrocytic TDP-43 mislocalization, even when occurring throughout
the brain [114], suggesting that TDP-43 pathology in astrocytes has region-selective effects on
brain function. Mutant huntingtin and tau also disturb astrocytic cholesterogenesis, which is
essential for neuronal function [115–117]. Therefore, heterogeneous proteinopathy in astrocytes,
along with local variations in BBB-linked clearance mechanisms, could result in selective
vulnerabilities in protein handling and specific types of neuronal and neurocognitive impair-
ments. In support, correlational analyses of Aβ, tau, and astrocyte pathology, as assessed
by plasma GFAP levels, suggest that astrocytic alterations in humans may reflect an early
pathogenic transition in preclinical AD, predicting tau pathology and thereby linking Aβ
accumulation to clinical symptoms [118].

Metabolic pathways
Neurodegenerative disorders also involve changes in astrocytic metabolic pathways [119–122].
Astrocytes supply essential metabolites to neurons and other cells, including lactate for energy,
cholesterol for membrane homeostasis, glutamine as a precursor for neurotransmitters, and
factors to maintain redox homeostasis [123,124]. Astrocytes also regulate cerebral blood flow
to sustain neuronal energy and potentially integrate peripheral metabolic cues [47,125].
Moreover, astrocyte subpopulations have been identified with varying expression of genes
involved in energy-producing processes, including glycolysis and oxidative phosphorylation,
functions that might be compromised in aging, according to transcriptomic studies in mice
[32,93], and these differential bioenergetic states could promote impairments in select circuits
or brain regions.

Alterations to astrocyte metabolism have multifactorial and context-dependent effects. In mouse

models, changes in astrocytic urea metabolism protect from Aβ toxicity but also result in GABA
overproduction and cognitive deficits [126]. Astrocytes also buffer neuronal fatty acid (FA)
lipotoxicity upon stress or increased neuronal firing [127,128]. However, in the context of HD-
linked pathology in mice, a metabolic shift toward FA oxidation in striatal astrocytes increases
the levels of reactive oxygen species (ROS) that promote disease [129]. By contrast, loss of the
ability to catabolize FAs can contribute to astrocyte reactivity in certain subpopulations and
cause neurotoxic FA release by mouse astrocytes [122,130,131]. ApoE expression, a key regu-
lator of lipid transport, is enriched in astrocytes as compared with other neural cell types, and
ApoE4 is a strong genetic risk factor for AD. ApoE4 diminishes astrocytic clearance of neuronal
lipids and degradation of FAs, thereby possibly contributing to lipid dysregulation and neuronal
metabolic stress [120,132]. In human induced pluripotent stem-cell (iPSC)-derived astrocytes,
ApoE4 also increases astrocytic cholesterol release that can exacerbate neuronal amyloid
precursor protein (APP) processing and Aβ production [133]. Thus, ApoE and other genetic
variants linked to disease risk can shift metabolic functions of astrocytes and promote specific
vulnerabilities. A better understanding is needed of the metabolic repertoire of different astrocyte
populations and states, and their respective capacity to respond to alterations in metabolic
supply and demand associated with disease. Of note, studies in mice increasingly link astrocyte
metabolism to cognitive function [134–136], suggesting that therapeutic targeting of these
mechanisms might reduce pathology as well as restore or enhance cognitive processes.

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Regional variations in cytoarchitecture and astrocytic–neurovascular contacts may also contribute

to localized or variable metabolic vulnerabilities. Astrocytic endfeet line capillaries throughout
the brain, enable neurovascular coupling, and modulate the flux of essential metabolites, waste
products, trophic factors, and other molecules across the BBB [137]. However, there are dif-
ferences in the degree of vessel coverage by astrocytes across brain regions [78]. Particularly,
mouse cortical astrocytes contact more vessels than hippocampal astrocytes, and a subset of
astrocytes without vessel contact have been detected in the hippocampus but not other examined
regions [138]. Hippocampal astrocytes are estimated to contact roughly 100 000 excitatory synap-
ses, whereas striatal astrocytes contact about half as many synapses [77]. Together, these findings
suggest that hippocampal astrocytes bear a larger load of excitatory synapses but contact fewer
blood vessels, which might cause insufficient energy supply and altered metabolic states upon
increases in neuronal activity and neural network dysregulation in disease [139]. Of note, astrocytes
in AD have enhanced connexin-43 expression, a gap junction channel that can connect adjacent
astrocytes [140], which may reflect a compensatory response to distribute the increased metabolic
load across a broader astrocyte network. Dynamic changes in astrocytic morphology could also
affect their physical interactions with the vasculature and synaptic elements. In mouse models,
disrupted metabolic supply can recruit astrocytic metabolic stores from nearby unstressed brain
areas, potentially leaving those areas more susceptible to stressors [141]. Hence, variations in
physical contacts and redistribution of metabolites across astrocyte networks could contribute
to differential and progressive susceptibility of healthy regions and the spread of pathology across
brain areas.

Neurotransmission and synaptic function

Astrocytes constitute an essential element of synaptic transmission and plasticity, and their
engagement in these processes is crucial for brain function [142]. In particular, astrocytes regu-
late neurotransmitter synthesis and cycling, and alterations in these mechanisms have profound
effects on neuronal function and vulnerability to disease [124,143]. In mouse and human iPSC-
based models of FTD with progranulin mutations, reduced glutamate uptake by astrocytes
promoted synaptic degeneration in thalamocortical circuits [106]. Additionally, reduced astrocytic
GABA uptake upon injury induces neuronal hyperexcitability in the thalamus [144], and astrocytic
GABA overproduction in transgenic mice with AD-related amyloid pathology impairs spike
probability in the hippocampus [143]. These astrocytic functions can vary across brain regions.
For instance, astrocytic glutamate uptake is faster in the mouse frontal cortex than in the somato-
sensory cortex [145], and vesicular glutamate is released by a specific subset of hippocampal and
cortical astrocytes that express genes required for calcium-regulated glutamate exocytosis, as
detected in mouse and human brains [50]. These specialized astrocytic functions might differen-
tially influence local changes in neurotransmission and synaptic plasticity in disease.

Astrocytes are also involved in maintaining synaptic structure and density through the release of
synaptogenic factors and active elimination of synapses. These functions can vary across regions
and types of synapses. In aging mice, a specific population of hippocampal astrocytes has
impaired autophagy and synaptogenic mechanisms for regulating synapses [109]. In a mouse
model of HD, dysfunctional Gi/o-coupled receptor signaling in striatal astrocytes can selectively
dysregulate synaptogenesis and cause impairments in attention-associated behaviors [88]. In
mouse models and human cases of ALS, a selective loss of tripartite synapses may occur,
pointing to greater vulnerability of synapses containing astrocytic processes as compared with
bipartite synapses [146]. Human and mouse astrocytes are also implicated in increased AD
pathology-associated synapse elimination [147]. Of note, astrocytic synapse elimination in a
mouse model of tauopathy preferentially targets excitatory synapses over inhibitory synapses,
which may be engulfed more by microglia [148]. Astrocytes can also modulate microglia-

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mediated synapse elimination [149] and could influence microglial roles in brain resilience to
tauopathy [31], but these potential astrocytic–microglial interactions require further investigation.
In addition to enhanced synapse removal, there is also evidence that astrocytes in transgenic
mice with amyloid pathology are impaired in the clearance of dystrophic synapses [150]. In
summary, astrocytes are known to influence synaptic structure and function, and recent studies
suggest that these effects are likely region-specific and selective, mediated by distinct astrocytic
subpopulations, differentially affected by pathogenic cascades, and potentially intertwined with
microglial activities.

Astrocytic context-dependent roles in disease may inform therapeutic approaches

As discussed earlier, astrocytes are essential for proper CNS function, and their molecular and
morphological features and functional properties vary across brain regions, circuits, and synap-
ses, and can strongly depend on the exact biological context and disease process. These diverse
and dynamic properties are likely due in large part to astrocytic sensitivity to numerous incoming
signals that provide information regarding animal maturity and age [93,109,151], biological sex
[152,153], genetic factors [121,154], metabolism [47,136,155], sensory inputs and arousal
[156], and various other brain activities and systemic factors. The integrated processing of local
and long-range signals likely generates a variety of astrocytic phenotypes and functional states
that are fine-tuned and integrated into their specific neural context. We speculate that ‘context in-
tegration’ enables astrocytes to properly support and modulate many different types of neural cir-
cuits, synapses, and functions in diverse and dynamic biological conditions (Figure 4). As
described in the previous section, astrocytes also have heterogeneous responses and selective
roles in neurodegenerative disease-associated pathogenic processes. Particularly, aberrant cues
and factors associated with aging, proteinopathy, inflammation, and other pathological
processes induce specific types of changes in subsets and subcompartments of astrocytes,
affecting their gene expression, protein handling, and immunometabolic pathways, and their
regulation of specific types of neuronal circuits, synapses, and other surrounding cells. These
changes result in dysfunctional engagement (or disengagement) of astrocytes in their defined
microenvironment, which we call ‘context divergence’. Shifting from context-integrated to
context-divergent states could set the stage for selective pathogenesis by preferentially
disrupting (or failing to maintain) specific astrocyte-regulated neural circuits, signaling mecha-
nisms, and local brain activities (Figure 4).

(A) Naive Context-integrated (B) Context-divergent

astrocytes Combinatorial astrocytes New inputs astrocytes
inputs or perturbations
B1, N8, M6, S2, O5, etc Disease, drugs, stress, etc.

Functionally diverse Additional complexity Selective Selective Widespread

Brain region Maturation and age and dynamic states ● timing of onset improvements disruptions disruptions
(B1, B2, ...Bx) (M1, M2, ...Mx)
● precise target(s)
Genetic variations Sex-related variables
(G1, G2, ...Gx) (S1, S2, ...Sx) ● stable or dynamic
Normal behavior Cross-context
Neuronal inputs Other glia, vasculature
(N1, N2, ...Nx) (O1, O2, ...Ox) and cognition enhancement impairment impairments

Trends in Neurosciences

Figure 4. Astrocytes promote context-dependent effects in health and disease. (A) Astrocytes are sensitive to various cues in their microenvironment and have
diverse molecular, structural, and functional states as a result of the specific combination of cues received by individual astrocytes. These combinatorial inputs instruct
astrocytes to assume various context-integrated states that enable normal brain function. (B) In disease and other conditions, aberrant inputs and perturbations affect
individual astrocytes differently and may shift subsets or subcompartments of astrocytes into context-divergent states that selectively enhance or disrupt specific
aspects of brain function. Figure created with BioRender.

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Further investigation of the exact molecular and cellular basis for selective vulnerability holds great Outstanding questions
potential for elucidating disease pathogenesis and developing more effective treatment options, The mechanisms by which astrocytes
with the possibility for earlier and more precise interventions. With regard to the contributions of regulate various types of disease
processes and neural impairments
astrocytes to disease progression, recent studies argue against the notion that disease-related
are incompletely understood. When
impairments are triggered largely by dysfunction in neuronal or other glial populations with and how do astrocytes engage
secondary or ancillary responses in astrocytes. Instead, studies are converging on a theory in different pathological cascades,
that dysfunctions in astrocytes are operating in concert with neuronal predispositions and poten- synaptic alterations, and neural circuit
dysfunctions?
tial abnormalities in other cells to trigger selective neurodegenerative cascades and progressive
behavioral alterations. It remains unclear whether astrocytes
are a diverse population with
Considering this emerging view, effective therapeutic strategies may require targeting of astrocytic developmentally defined and constant
states, whether they exhibit dynamic
functions that are linked to specific neuronal circuits most susceptible to impairment in a particular
shifts in function that generate
type of disorder and patient population. Whether targeting a discrete disease-associated astrocyte apparent heterogeneity, or whether
subcluster or a broader astrocyte network within a given brain region is required for therapeutic both scenarios are occurring in vivo.
efficacy remains an important open question. Further investigations are required to unravel exactly What are the exact triggers and
regulatory mechanisms that promote
how different astrocytic subpopulations, compartments, and functional states are organized and regional astrocyte heterogeneity in
dynamically tuned to different brain activities, and how these astrocytic states are selectively health and disease?
compromised and could be therapeutically targeted in neurodegenerative conditions.
What are the effects of disease-
linked astrocytic changes on specific
Concluding remarks and future perspectives neuronal subpopulations that are
Mounting evidence of astrocytic heterogeneity and functional selectivity suggests that astrocytes known to be most vulnerable to dis-
could promote selective vulnerability in disease. Significant progress has been made in broadly ease? What is the nature of astrocyte
contributions to cognitive and behavioral
profiling molecular changes and uncovering novel mechanisms that mediate astrocytic–neuronal
deficits across disorders and what
crosstalk and effects on pathogenic processes. However, an integrated understanding of are their specific pathophysiological
astrocytic and neuronal functions and their interconnected changes in disease is still lacking. mechanisms?
Additional studies are needed that address how astrocytes differentially regulate and contribute
Individual astrocytes have structural
to brain function and pathology in distinct biological and environmental contexts (see and functional subcompartments,
Outstanding questions). In elucidating these roles, it is important to be mindful of the limitations including endfeet and leaflets. What
of current models of neurodegenerative disorders and to explore neuropathological evidence are the disease-linked changes in
and multiomic datasets from human samples and use human iPSC-derived systems when these subcellular compartments,
and how do these changes affect
possible. Human astrocytes can differ from mouse astrocytes in certain morphological features, presynaptic and postsynaptic ele-
metabolic changes, and inflammatory pathways, emphasizing the importance of cross-species ments, neurovascular cells, and other
validation [157,158]. Future studies should investigate the roles of circuit-specific and molecularly glia?
defined subpopulations of astrocytes, take advantage of advanced genetically encoded indica-
Astrocytes are the primary cell type
tors and actuators, and rigorously compare astrocytic features and functions across different bi- involved in the synthesis of brain
ological and pathogenic contexts. lipoproteins and lipids, including ApoE
and cholesterol, which are essential
for brain function and implicated in
Acknowledgments
neurodegenerative disorders. How is
This work was supported by the National Institutes of Health: R01AG068091 (A.G.O.) and RF1NS118569 (A.G.O.),
astrocytic lipid metabolism and lipid-
BrightFocus Foundation: BFA2023008F (T.S.Z.), and the Alzheimer’s Association: 23AARF-1029892 (T.S.Z.). based crosstalk with other cell types
regulated by neuronal and neurovascular
Declaration of interests activities and altered by pathological
The authors declare no competing interests in relation to this work. processes?

Sex differences affect behavioral and

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