Lysosomal acidification impairment in astrocyte-mediated neuroinflammation

Abstract

Astrocytes are a major cell type in the central nervous system (CNS) that play a key role in regulating homeostatic functions, responding to injuries, and maintaining the blood-brain barrier. Astrocytes also regulate neuronal functions and survival by modulating myelination and degradation of pathological toxic protein aggregates. Astrocytes have recently been proposed to possess both autophagic activity and active phagocytic capability which largely depend on sufficiently acidified lysosomes for complete degradation of cellular cargos. Defective lysosomal acidification in astrocytes impairs their autophagic and phagocytic functions, resulting in the accumulation of cellular debris, excessive myelin and lipids, and toxic protein aggregates, which ultimately contributes to the propagation of neuroinflammation and neurodegenerative pathology. Restoration of lysosomal acidification in impaired astrocytes represent new neuroprotective strategy and therapeutic direction. In this review, we summarize pathogenic factors, including neuroinflammatory signaling, metabolic stressors, myelin and lipid mediated toxicity, and toxic protein aggregates, that contribute to lysosomal acidification impairment and associated autophagic and phagocytic dysfunction in astrocytes. We discuss the role of lysosomal acidification dysfunction in astrocyte-mediated neuroinflammation primarily in the context of neurodegenerative diseases along with other brain injuries. We then highlight re-acidification of impaired lysosomes as a therapeutic strategy to restore autophagic and phagocytic functions as well as lysosomal degradative capacity in astrocytes. We conclude by providing future perspectives on the role of astrocytes as phagocytes and their crosstalk with other CNS cells to impart neurodegenerative or neuroprotective effects.

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Zeng et al. Journal of Neuroinammation (2025) 22:72
https://doi.org/10.1186/s12974-025-03410-w
Introduction
Astrocytes are a major class of glial cells found in the cen-
tral nervous system (CNS), representing 19 to 40% of the
glial population [1]. Under normal condition, astrocytes
are responsible for maintaining homeostasis including
regulation of ion and water balance [2], maintenance of
the blood-brain barrier (BBB) [3], and regulation of local
cerebral blood ow [2, 3] (Fig. 1A-C). Astrocytes also
help to provide support for neuronal metabolic functions
[4] and maintain synaptic homeostasis through modulat-
ing synaptic formation, maturation, and elimination [5,
6] (Fig.1D-E). Furthermore, astrocytes play key roles in
Journal of Neuroinammation
†Jialiu Zeng and Jonathan Indajang contributed equally to this work.
*Correspondence:
Jialiu Zeng
jzeng22@syr.edu
Chih Hung Lo
clo101@syr.edu
1Department of Biomedical and Chemical Engineering, Syracuse
University, Syracuse, NY 13244, USA
2Interdisciplinary Neuroscience Program, Syracuse University, Syracuse,
NY 13244, USA
3Meinig School of Biomedical Engineering, Cornell University, Ithaca,
NY 14853, USA
4Department of Neurology, Yale School of Medicine, New Haven,
CT 06511, USA
5Department of Biology, Syracuse University, Syracuse, NY 13244, USA
Abstract
Astrocytes are a major cell type in the central nervous system (CNS) that play a key role in regulating homeostatic
functions, responding to injuries, and maintaining the blood-brain barrier. Astrocytes also regulate neuronal
functions and survival by modulating myelination and degradation of pathological toxic protein aggregates.
Astrocytes have recently been proposed to possess both autophagic activity and active phagocytic capability
which largely depend on suciently acidied lysosomes for complete degradation of cellular cargos. Defective
lysosomal acidication in astrocytes impairs their autophagic and phagocytic functions, resulting in the
accumulation of cellular debris, excessive myelin and lipids, and toxic protein aggregates, which ultimately
contributes to the propagation of neuroinammation and neurodegenerative pathology. Restoration of lysosomal
acidication in impaired astrocytes represent new neuroprotective strategy and therapeutic direction. In this
review, we summarize pathogenic factors, including neuroinammatory signaling, metabolic stressors, myelin and
lipid mediated toxicity, and toxic protein aggregates, that contribute to lysosomal acidication impairment and
associated autophagic and phagocytic dysfunction in astrocytes. We discuss the role of lysosomal acidication
dysfunction in astrocyte-mediated neuroinammation primarily in the context of neurodegenerative diseases along
with other brain injuries. We then highlight re-acidication of impaired lysosomes as a therapeutic strategy to
restore autophagic and phagocytic functions as well as lysosomal degradative capacity in astrocytes. We conclude
by providing future perspectives on the role of astrocytes as phagocytes and their crosstalk with other CNS cells to
impart neurodegenerative or neuroprotective eects.
Keywords Lysosomal acidication, Lysosomal alkalization, Autophagy, Phagocytosis, Metabolic dysfunction, Acidic
nanoparticles, Glial crosstalk, Neurodegeneration, Neuroinammation, Neuroprotective
Lysosomal acidication impairment
in astrocyte-mediated neuroinammation
JialiuZeng1,2*†, JonathanIndajang3†, DavidPitt4 and Chih HungLo2,5*
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Zeng et al. Journal of Neuroinammation (2025) 22:72
phagocytic uptake of cellular debris, myelin/lipids, and
toxic protein aggregates [7, 8] as well as modulation of
neuroimmune responses [9] (Fig. 1F-G). Upon expo-
sure to external stimuli, astrocytes become reactive and
exhibit cellular heterogeneity, including alterations in
cell morphology and functions, gene expression proles,
cytokine production levels, as well as their response to
injuries, which have implications towards brain inam-
mation and neuronal death [10–14].
Recent studies have highlighted that autophagic and
phagocytic processes play key regulatory roles in astro-
cytic degradation capability and impairments in these
functions could contribute to neuroinammation and
neurodegeneration [15–17]. In addition to the process-
ing of external cargo by phagocytosis [18], the processing
of internal cargo by autophagy is important in astrocyte
dierentiation and maturation as well as regulation of
mitochondrial dynamics, reactive oxygen species (ROS)
generation, neuroimmune response, and cell death [19].
In astrocyte autophagy and phagocytosis, fusion of
autophagosomes and phagosomes with suciently acidi-
ed lysosomes as maintained by the lysosomal vacuolar
(H+)-ATPase (V-ATPase) is essential for their degrada-
tive functions [20]. In the homeostatic state, astrocyte
autophagy and phagocytosis are functional in the pres-
ence of optimal lysosomal acidication and these pro-
cesses maintain cellular homeostasis, support axonal
health, and regulate myelination, contributing to neuro-
nal plasticity, functions, and survival [21, 22] (Fig.2A).
In their reactive states, it has been demonstrated that
an elevation of lysosomal pH or defective lysosomal
acidication decreases the eciency and eectiveness of
Fig. 1 The multifaceted roles of astrocytes in the brain. (A) Astrocytes control ion homeostasis and water exchange in the brain microenvironment by
regulating channel proteins including aquaporin-4 (AQP4) water channel as well as potassium, sodium, and calcium channels. (B) Astrocytes support the
formation of tight junctions (e.g., claudin, occludin, junctional adhesion molecules (JAM), and cadherin) and the maintenance of epithelial cells at the
blood-brain barrier (BBB). (C) Contraction and blood ow movement of the BBB is mediated by smooth muscle tissue that respond to Ca2+ ions released
and regulated by astrocytes. (D) Astrocytes mediate nutrient transport to neurons to regulate neuronal metabolism. (E) Astrocytes operate as phagocytes
to carry out synaptic pruning as well as remove cell debris, damaged organelles, and myelin. (F) Astrocytes participate in autophagic degradation of intra-
cellular toxic protein aggregates, myelin/lipids and cellular debris phagocytosed from damaged neurons. (G) Astrocytes release inammatory cytokines
that can recruit microglia to sites of brain injury and/or induce neuronal impairment and death. The gure was created with BioRender.com
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Zeng et al. Journal of Neuroinammation (2025) 22:72
astrocytes to perform autophagic and phagocytic func-
tions [23, 24]. e resulting accumulation of damaged
organelles, myelin debris, and toxic protein aggregates as
well as the release of inhibitory factors and ROS further
propagate neuroinammation and drive neurodegenera-
tion [25, 26] (Fig.2B). Under aging or diseased condi-
tions, there are evidence of synaptic and autophagosomal
proteins as well as toxic protein aggregates accumulated
and colocalized with poorly acidied lysosomes in reac-
tive astrocytes [27–30]. However, the role of dierent
stimuli and their molecular mechanisms associated with
lysosomal acidication impairment in astrocytes are
unclear and remain to be claried. While the accumu-
lation of unwanted and toxic materials may be a conse-
quence of lysosomal dysfunction, it is important to note
that these materials could also be the initial triggers in
impairing lysosomal acidication.
In this review, we summarize the role of neuroinam-
matory signaling, metabolic stressors, myelin and lipid
mediated toxicity, and toxic protein aggregates in lyso-
somal acidication impairment and associated autopha-
gic and phagocytic dysfunction in astrocytes (Fig.3). We
discuss these pathogenic factors primarily in the context
of neurodegenerative diseases along with other brain
injuries that provide insights to the role of lysosomal
acidication dysfunction in astrocyte-mediated neuroin-
ammation. We provide some insight into the feedback
mechanisms between pathogenic factors and lysosomal
dysregulation, both regarding how astrocytic dysregula-
tion is initiated by pathogenic factors, and how eventual
dysregulation accelerates neural degeneration. We then
highlight current therapeutic strategies to re-acidify lyso-
somes and restore astrocyte autophagic and phagocytic
functions. We conclude by providing future perspectives
on the role of astrocytes as phagocytes and their coopera-
tive role with other CNS cells such as microglia and neu-
rons to mediate neurodegeneration and neuroprotection.
Fig. 2 Autophagic and phagocytic degradative functions in normal and reactive astrocytes. (A) In normal astrocytes, lysosomes maintain a suciently
acidic environment, enabling proper vesicle fusion and optimal autophagic/phagocytic activities, including the clearance of damaged mitochondria and
myelin debris, thereby maintaining neuronal health. In addition, astrocytes release regenerative factors which contribute to neuron remyelination. (B)
In reactive astrocytes under exposure to pro-inammatory cytokines, excessive lipids, and toxic protein aggregates, lysosomal acidication is impaired
(poorly acidied lysosomes), leading to inhibition of autophagic/phagocytic activities. As a result, there is reduced mitochondrial turnover and increased
accumulation of damaged mitochondria, as well as release of neurotoxic factors such as ROS. In addition, damaged astrocytes can release undegraded
toxic materials as well as inhibitory factors that further impair neuronal function. Re-acidication of impaired lysosomes by lysosome-targeting small
molecules and nanoparticles restores autophagic/phagocytic functions in astrocytes, allowing for eective clearance of neurotoxic factors to maintain
neuronal health. The gure was created with BioRender.com
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Zeng et al. Journal of Neuroinammation (2025) 22:72
Neuroinammatory signaling
Inammatory reactive astrocytes with reduced homeo-
static functions can be neurotoxic, contributing to neu-
rodegenerative diseases including Alzheimer’s disease
(AD), Parkinson’s disease (PD), and multiple sclerosis
(MS). Reactive astrocytes subjected to microglia-derived
pro-inammatory cytokines such as a combination of
tumor necrosis factor (TNF), interleukin-1α (IL-1α), and
complement component 1q (C1q) have reduced abil-
ity to promote neuronal survival, synaptogenesis and
Fig. 3 Factors aecting lysosomal acidication dysfunction in astrocytes. (A) Exposure to dierent cytokines triggers neuroinammatory signaling that
induce diverse astrocyte inammatory phenotypes. Cytokines exposure leads to a reduction of lysosomal V-ATPase levels, leading to elevated lysosomal
pH and reduced lysosomal enzyme degradative capacity. Chronic autolysosomal buildup due to incomplete degradation leads to exocytosis of neu-
rotoxic factors which impair surrounding neurons. (B) Changes in nutrient levels induce metabolic stress which lead to mitochondrial dysfunction and
impaired lysosomal acidication. (C) In astrocytes with lipids or myelin accumulation, lysosomal size is increased along with elevated lysosomal pH. In
addition, high fat diet intake and metabolic disorders that aect the peripheral organs can also aect astrocyte function and reactivity. (D) Toxic proteins
aggregates taken up by astrocytes localized into lysosomes and impaired lysosomal acidication, resulting in cellular dysfunction and spreading of pa-
thology due to inecient degradation and increased release of the toxic materials. The gure was created with BioRender.com
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Zeng et al. Journal of Neuroinammation (2025) 22:72
phagocytosis, and can induce neuronal death in human
AD, PD and MS tissues [31]. Dierent cytokine cocktails
may induce dierent astrocyte phenotypes which could
be neurotoxic or neuroprotective [31–33]. Defective lyso-
somal acidication has been shown to be associated with
neurotoxic reactive astrocytes, age-related inammation,
and consequentially contribute to neurodegenerative dis-
eases [33, 34] (Fig.3A).
CRISPR interference screens were conducted on
human-induced pluripotent stem cells (hiPSC)-derived
astrocytes cultured with microglia-derived pro neu-
roinammatory cytokines (TNF, IL-1α, and C1q) to
determine relevant pathways propagating inamma-
tory astrocyte reactivity [32]. IL-6 and interferon signal-
ing downstream of canonical NF-κB activation drove
two distinct inammatory reactive signatures, and both
are modulated by the signal transducer and activator of
transcription 3 (STAT3). ese signatures were vali-
dated in both mouse models and in human AD brains
[32]. In addition, genes involved in the mammalian tar-
get of rapamycin (mTOR) pathway were found to be sig-
nicantly changed [32]. In a follow-up study by the same
group, CRISPR interference screens were conducted on
human iPSC-derived astrocytes treated with pro-inam-
matory cytokines (e.g., TNF, IL-1α, and C1q) to identify
molecular targets that aects lysosomal acidication dys-
function and exocytosis [33]. First, signicant lysosomal
alkalization and autophagic dysfunction were observed
in neurotoxic reactive astrocytes. Lysosomal alkaliza-
tion has been attributed to multiple downregulated genes
including V-ATPase subunits and lysosomal hydrolases
[33]. Importantly, it was found that mTOR is a central
upstream regulator of this phenotype which is linked
to lysosomal acidication dysfunction in inammatory
reactive astrocytes [33]. Inhibition of mTOR restored
lysosomal acidication and rescued this phenotype
associated with neurodegenerative diseases [33]. More-
over, these reactive astrocytes have increased lysosome
exocytosis, leading to the secretion of toxic materials.
In inammatory reactive astrocytes, mTOR activation
remodels lysosomal functions and induces unconven-
tional secretion of IL-32 which is involved in the polar-
ization of astrocyte reactive states [35], while mTOR
inhibition reduces the intracellular levels and secretion
of lipocalin-2 [36]. However, the relationship between
whether the secreted materials directly mediate neuronal
toxicity or if the materials contribute to toxicity through
an indirect mechanism such as autocrine-paracrine sig-
naling, remains to be elucidated. Emerging evidence indi-
cates that mTOR activity is age-dependent, with aged
and senescent astrocytes exhibiting distinct transcrip-
tional proles compared to other astrocytic populations
[37, 38]. In aging astrocytes, reduced mTOR activity
disrupts autophagy and lysosomal function, leading to
protein tracking defects and impaired synapse regu-
lation. A subset of aging astrocytes, termed autophagy-
dysregulated astrocytes, displays lysosomal dysfunction,
abnormal autophagosome accumulation, and impaired
proteasome function, resulting in synapse loss and
reduced dendritic spines [37]. While senescent astrocytes
exhibit proinammatory proles partly driven by active
mTOR signaling and DNA-damage response pathways
[38], these ndings highlight the shifting roles of mTOR
in aging astrocytes and its potential as a therapeutic tar-
get in neurodegenerative diseases.
In other disease contexts, it was shown that the stim-
ulation of toll-like receptor 3 (TLR3) triggers lysosomal
alkalization and release of adenosine triphosphate (ATP)
and luminal contents from optic nerve head astrocytes
[39]. In MS patients and mice, a subset of astrocytes that
expresses the lysosomal protein LAMP1 and the TNF-
related apoptosis-inducing ligand (TRAIL) has been
identied [40], bridging the link between lysosomal dys-
function and astrocyte-mediated neuroinammation. In
a lysosomal storage disease model of astrocytes, there
is progressive neuroinammatory response and inhi-
bition of autophagic function [41]. In addition, in Gau-
cher disease patients derived induced astrocytes, there is
reduced glucocerebrosidase activity, cathepsin D activ-
ity, and increased inammatory response [42]. In corti-
cal astrocytes isolated from mice with multiple sulfatase
deciency, there is impaired lysosomal/autophagic dys-
function and accumulation of autophagic substrates [43].
ere are also examples of activation of autophagy func-
tions in astrocytes to attenuate inammasome activa-
tion or inammatory phenotypes in neurodegenerative
diseases [44, 45]. Hence, the crosstalk between autoly-
sosomal acidication dysfunction and neuroinamma-
tion, and their pathogenic roles in neurodegenerative and
neuroimmune disorders warrant further investigations. It
is important to design future studies around the goal of
examining the association between autolysosomal acidi-
cation dysfunction and neuroinammation in heterog-
enous cell cultures or in vivo.
Metabolic stressors
Astrocytes and neurons operate as a tightly coupled unit
for energy metabolism in the brain. As neurons expend
a considerable amount of ATP on neurotransmission,
astrocytic mitochondrial metabolism can release signal-
ing molecules like ATP and glutamate, allowing neurons
to allocate more cellular resources to sustain high activ-
ity rates during information processing [46, 47]. Dys-
functional astrocytic mitochondria can lead to impaired
glutamate clearance and increased levels of extracel-
lular glutamate, ultimately inducing glutamate toxic-
ity in neighboring neurons [48]. Furthermore, impaired
mitochondria in astrocytes can also lead to increased
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Zeng et al. Journal of Neuroinammation (2025) 22:72
ROS production or mitochondrial-derived damage-
associated molecular patterns into the cytoplasm, which
can also result in neuronal death [48, 49]. Hence, main-
taining astrocytic mitochondrial function is essential to
protect against neurodegeneration. Importantly, optimal
lysosomal acidication maintains the turnover of dam-
aged mitochondria through autophagic clearance, closely
regulating mitochondrial metabolism in astrocytes [50,
51]. On the other hand, mitochondria regulate lysosomal
pH by supplying ATP to activate the V-ATPase to acidify
the lysosomal lumen [52]. erefore, understanding and
maintaining proper mitochondria-lysosome crosstalk is
crucial to regulating astrocytic function (Fig.3B).
Chronic exposure to diet derived metabolites like
homocysteine and glucose aect astrocyte function.
Exposure to homocysteine, a homologue of the amino
acid cysteine, in astrocytes leads to lysosomal and
autophagic impairments, including lysosomal acidica-
tion dysfunction due to downregulation of V-ATPase
[53]. is further leads to increased oxidative stress and
astrocytic cell death [53]. Chronic exposure to high levels
of glucose in astrocytes induce mitochondrial oxidative
stress through 5’AMP-activated protein kinase-indepen-
dent pathways and lead to inhibition of transcription fac-
tor EB (TFEB) [54]. is consequently leads to impaired
lysosomal acidication, reduced phagocytic function, and
accumulation of oligomeric Aβ in astrocytes [54]. Expo-
sure to high glucose has also been reported to promote
ferroptosis of astrocytes by disrupting iron metabolism,
which can be rescued by administration of gembro-
zil, a peroxisome proliferator-activated receptor alpha
(PPARα) agonist. Gembrozil prevented the accumula-
tion of lipid peroxidation products and ROS induced by
iron deposition in astrocytes and inhibited ferroptosis of
astrocytes [55]. Gembrozil has been shown to upregu-
late TFEB and enhance lysosomal biogenesis in astrocytes
via PPARα [55], suggesting that lysosomal acidication
may play an important role in alleviating high glucose
induced metabolic dysfunction in astrocytes.
In a brain ischemia mouse model, increased expression
of inammatory cytokines TNF and IL-1β was seen in
astrocytes. Using an oxygen-glucose deprivation/reoxy-
genation (OGD/R) model of primary mouse astrocytes to
study brain ischemia in vitro, lysosomal impairment and
autophagic dysfunction were observed, as determined by
decreased lysosome number, increased lysosomal size,
and accumulation of autophagosome associated pro-
teins [56]. In a OGD primary rat astrocytes model, it was
shown that there is an increase in lysosomal membrane
permeabilization (LMP) and cathepsin release from lyso-
somes into the cytoplasm of astrocytes, leading to cell
death [57]. is was also seen in another study using a
similar model [58], alongside with disrupted mitochon-
drial membrane potential, increased production of ROS
and inammatory cytokines TNF, IL-6 and FasL, as well
as apoptosis in astrocytes [58]. e knockdown of recep-
tor interacting protein 1, an essential molecule in medi-
ating TNF signaling, blocked OGD-induced increase in
LMP and astrocyte death, suggesting that TNF down-
stream pathways contribute to lysosomal dysfunction in
ischemic astrocytes [57]. In another instance, conditional
knockdown of LAMP-2A in ischemic astrocytes inhib-
ited their activation and prevented the translocation of
the pro-apoptotic proteins Bax and Bad to mitochon-
dria, thereby preventing neuronal death, suggesting that
elevated astrocytic LAMP-2 A contributes to ischemic
vulnerability.
Myelin and lipid induced toxicity and dysfunction
Astrocytes are actively involved in lipid metabolism in
the brain and can be aected by increased levels of sat-
urated fatty acids associated with dysfunctional lipid
metabolism, neuronal myelin damage, and obesity [59–
61]. Cultured brain astrocytes present higher capacity
to process lipids in their oxidative metabolism and have
a higher propensity to uptake fatty acids than other cell
types in the brain [62]. e sensitivity of astrocytes and
their reactive state transformation under lipid-induced
oxidative stress such as sphingosine-1-phosphate (S1P)
and apolipoprotein E (APOE) mutations, myelin debris
accumulation and chronic exposure to fatty acids could
lead to failure in their functions (Fig.3C). S1P is a bio-
active signaling lipid involved in several vital processes,
including cellular proliferation, survival, and migration.
Autosomal recessive mutations in sphingosine-1-phos-
phate lyase 1 which encodes for S1P lyase, leads to neu-
rodevelopmental disorders. An excess of S1P due to
mutations in S1P lyase led to increased activity of regu-
latory enzymes involved in the tricarboxylic acid cycle
and increased cellular ATP content, which subsequently
activated mTOR and reduced lysosomal-autophagosome
fusion as well as reduced autophagic function of astro-
cytes [63]. Phospholysine phosphohistidine inorganic
pyrophosphate phosphatase (LHPP) is another enzyme
that is highly expressed in the brain which catalyzes
pyrophosphate to orthophosphate. LHPP is primarily
expressed in the lysosomes of astrocytes and has opti-
mal enzymatic activity at an acidic pH [64]. Under stress
conditions, LHPP modulates lysosomal acidication
through pyrophosphate hydrolysis driven proton trans-
port through the V-ATPase, thereby averting the adverse
impact of chronic stress on adult hippocampal neurogen-
esis [64].
Apolipoprotein E (ApoE) plays a major role in choles-
terol and phospholipid regulation within the CNS [65]
and astrocytes are the primary source of ApoE in the
brain [66]. e E4 allele of APOE (APOE4) is the stron-
gest genetic risk factor for the development of late onset
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Zeng et al. Journal of Neuroinammation (2025) 22:72
AD. APOE4 astrocytes accumulate high amounts of lipid
droplets and have decreased fatty acid uptake and oxi-
dation compared to APOE3 astrocytes [67]. is obser-
vation is also consistent with other reports related to
lysosomal dysfunctions associated with APOE4 astro-
cytes [68], with a specic study illustrating that lyso-
somes in APOE4 astrocytes have a higher lysosomal pH
than APOE3 astrocytes [69]. APOE4 also downregulates
the sodium-hydrogen exchanger 6, which create dys-
regulation of the endosomal pH in astrocytes, leading to
Aβ accumulation within the astrocytes [70]. e impair-
ments of endolysosomal and autophagic function in
APOE4 astrocytes has also been reported in other studies
[69, 71, 72]. In addition, APOE4 astrocytes induce cho-
lesterol accumulation that impairs lysosomal turnover
of damaged mitochondria and treatment of therapeutic
agents that remove cholesterol restores autophagic and
mitochondrial activity [73].
In the CNS, myelin uptake is thought to occur primar-
ily by microglia. However, recent studies have shown that
astrocytes also participate in this process [74, 75]. Astro-
cytes actively phagocytose myelin debris during demy-
elination [76, 77]. In a study using primary rat astrocytes
culture, the myelin debris was taken up by astrocytes
through receptor-mediated endocytosis and are trans-
ported to lysosomes for degradation. Exposure to exces-
sive myelin debris resulted in astroglial nuclear factor
kappa B (NF-κB) activation and secretion of inamma-
tory cytokines [76]. ese ndings were conrmed in
the context of MS, where myelin-positive astrocytes had
increased nuclear localization of NF-κB and cytokine
expression compared to astrocytes lacking myelin [76].
In a similar astrocyte culture model of spinal cord injury,
engulfed myelin debris are transported to lysosomes for
degradation and led to an increase in lysosomal size,
which consequently resulted in excessive glia scar forma-
tion [77]. Apart from myelin debris accumulation, accu-
mulation of cholesterol can also lead to impairment of
lysosomal acidication and increased lysosomal leakiness
in foamy phagocytes, which can eventually lead to cell
death [78].
Chronic exposure of fatty acid (e.g., palmitic acid) in
astrocytes have led to intracellular lipid accumulation
with an elevation of the pH in the lysosomes along with
autophagic dysfunction, and an increase in the mRNA
expression of pro-inammatory cytokines [79]. High-
fat diet (HFD) feeding induces peripheral obesity which
develops inammation and has been shown to aect
CNS function [80, 81]. In mice under HFD, there is
increased hypothalamic inammatory signaling, reactive
astrogliosis and microgliosis, along with neuronal injury
[82]. In a similar study, HFD feeding to mice reduced
mitochondrial number and increased mitochondrial size,
thereby contributing to reduced activity of hypothalamic
astrocytes [83]. In addition, there are other models of
liver related injury or inammation that has been found
to lead to neurodegeneration [80]. For instance, in alco-
holic liver disease mouse model, exposure to ethanol
impaired lysosomal acidication and function in astro-
cytes and reduced autophagic function [84]. In a hepatic
encephalopathy model where mice are exposed to high
levels of ammonia, astrocytes had decreased lysosomal
acidication and increased accumulation of ROS [85],
leading to neuronal toxicity. ROS has been shown to fur-
ther interact with lysosomal membranes through per-
oxidation, which destabilizes the membrane [86], leading
to decreased ecacy of proton pumps and pH “leaking”,
which would impair lysosomal acidication [86, 87].
Toxic protein aggregates
Astrocytes play a key role in the clearance of toxic protein
aggregates that are hallmarks of many neurodegenera-
tive diseases [88–91]. However, they are still vulnerable
to the toxic eects of protein aggregation in both familial
and sporadic pathologies, which have been implicated in
lysosomal dysfunction, autophagic inhibition, and propa-
gation of neurodegenerative pathology (Fig.3D). In AD,
accumulation of toxic aggregates such as amyloid beta
(Aβ) has been attributed to astrocytes dysfunction [92].
Presenilin-1 (PS1) mutation has been shown to impair
lysosomal vesicle tracking, leading to reduced degrada-
tion capacity, and accumulation of Aβ brils in astrocytes
[93]. APP/PS1 transgenic mice displayed a higher density
of astrocytes and increased accumulation of lysosomes
in cells, potentially due to a higher phagocytic activity
required to clear a higher burden of toxic materials in
the mice [94]. e stimulation of lysosomal biogenesis
with TFEB in astrocytes has been shown to reduce Aβ
plaque load in the hippocampus of APP/PS1 mice [95].
Another study has shown that a small molecule agonist
of angiotensin-(1–7) receptor (AVE 0991) could suppress
astrocyte neuroinammatory responses by enhancing
autophagy. Treatment of AVE 0991 reduced Aβ deposi-
tion as well as rescued neuronal death and cognitive de-
cits in APP/PS1 mice [96].
Human iPSC-derived astrocytes or primary astrocytes
exposed to Aβ brils or oligomers showed accumulation
of Aβ inclusions that were enclosed within LAMP1-pos-
itive lysosomes and sustained markers associated with
reactivity [97, 98]. Additionally, Aβ uptake and accumu-
lation in astrocytes resulted in endoplasmic reticulum
and mitochondrial swelling, autolysosomal dysregula-
tion, LMP, formation of pathological lipid structures, and
increased secretion of chemokines and cytokines [97,
99, 100]. Furthermore, increasing evidence have pointed
to the role of astrocytes in Aβ brils uptake and aggre-
gation, leading to indirect neurotoxic qualities [101,
102]. Specically, high level of glycoprotein YKL-40
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Zeng et al. Journal of Neuroinammation (2025) 22:72
in astrocytes can promote neurotoxicity and YKL-40
knockout astrocytes exhibit enhanced lysosomal acidi-
cation as well as increased uptake and degradation of Aβ
peptides [103]. In a study using neuron-astrocyte co-cul-
tures, it was shown that incomplete astrocyte phagocyto-
sis of Aβ brils leads to increased astrocytic secretion of
toxic vesicles as well as accumulation of Aβ brils in neu-
rons and neuronal cell death [101]. Ineective clearance
in astrocytes is possibly attributed to increased levels of
Rab27a protein, which reduces lysosomal acidity through
Nox2 recruitment [101]. In addition, increasing levels of
autophagic ux in astrocytes via progesterone has been
shown to be eective in enhancing the neuroprotective
and anti-inammatory eect of astrocytes in models of
AD [104]. Furthermore, stimulation of autophagy with
Sirtuin-1 in primary rat astrocytes has also been shown
to improve lysosomal function through upregulation of
V-ATPase subunits and increase in lysosome number,
leading to more eective clearance of Aβ brils [105].
In primary human astrocytes exposed to preformed 4R
tau brils, the endocytosis of tau aggregates causes lyso-
somal swelling, permeabilization, and lysosomal deacidi-
cation [106]. In primary mouse astrocytes treated with
tau pre-formed brils, expression of TFEB enhanced
lysosomal activity, increased tau degradation and inhib-
ited tau transmission [107]. TFEB activation enhances
the phagocytic capacity of astrocytes, through increas-
ing the uptake of pre-formed brils, and increases the
incidence of phagocytosed pre-formed brils inside the
lysosome, indicating that TFEB enhances both uptake
and degradation of phagocytosed proteins [107]. In addi-
tion, astroglial TFEB overexpression reduced tau pathol-
ogy, spreading, and gliosis in the hippocampus of PS19
tauopathy mice [107]. Studies in another tauopathy
model using rTg4510 tau transgenic mouse have also
shown that TFEB expression enhanced lysosomal activity
and clearance of autophagic substrates and phosphory-
lated tau [108]. Another study from the same group high-
lights TFEB’s role in mediating the lysosomal exocytosis
of mutant truncated tau, both in vitro and in PS19 trans-
genic mice. is process, dependent on the lysosomal
target TRPML1, is positively correlated with tau clear-
ance. Loss of TFEB increases tau pathology and spread-
ing, suggesting that TFEB-mediated lysosomal exocytosis
of tau acts as a clearance mechanism to reduce intracel-
lular tau under pathological conditions [109].
In PD, α-synuclein is the major component of neuro-
nal cytoplasmic aggregates called Lewy bodies, which
are the main pathological hallmark of the disease. In
immortalized astrocyte cell lines, overexpression of
wild-type α-synuclein as well as A30P and A53T mutant
α-synuclein led to inhibition of autophagy, loss of mito-
chondrial membrane potential, and cell death [110]. Pri-
mary astrocytes with A53T α-synuclein overexpression
or treatment with α-synuclein aggregates had decreased
lysosomal acidication and reduced lysosomal enzyme
activity, thereby contributing to the release of more
extracellular vesicles which propagate PD pathology
[111]. Incubation of astrocytes with Lewy body extracts
from human PD patients or α-synuclein preformed brils
led to α-synuclein colocalization in lysosomes, indicating
aggregate buildup due to reduced lysosomal degradative
capacity [112, 113]. Additionally, there is increased mito-
chondrial driven cytotoxicity in astrocytes [112]. Dose
dependent treatment with lysosomal V-ATPase inhibitor
Balomycin A1 led to an increase in the accumulation
of α-synuclein brils in astrocytes, indicating that lyso-
somal acidication plays an important role in modulating
α-synuclein buildup in astrocytes [114]. Increasing levels
of autophagic ux in astrocytes via rapamycin have been
shown to be eective in enhancing the neuroprotective
and anti-inammatory eect of astrocytes in models
of PD [115]. In other types of familial PD, mutations in
LRRK2, ATP13A2, GBA1, and PARK7 impair lysosomal
function and degradative capacity of astrocytes [42,
116–118]. LRRK2 G2019S primary mouse astrocytes
have enlarged lysosomes and abnormal lysosomal pH,
which led to reduced lysosomal activity, and is regulated
by LRRK2 localization to lysosomes [116]. Inhibition of
LRRK2 kinase activity with PF-06447475 restored defects
in lysosomal morphology and function [116]. ATP13A2
mutations in astrocytes resulted in decreased lysosomal
proteolysis function and increased accumulation and
propagation of α-synuclein [117]. Patient derived induced
astrocytes with GBA mutations also exhibited impaired
lysosomal enzyme activity, leading to α-synuclein accu-
mulation [42]. In DJ1 knockout iPSC-derived midbrain
organoid models, impaired lysosomal proteolysis results
in increased α-synuclein phosphorylation, protein aggre-
gation, and the accumulation of advanced glycation end
products. Astrocytes play a role in these eects, as DJ1
loss diminishes their metabolic support capacity and
promotes a pro-inammatory phenotype. In co-culture
models, DJ1-expressing astrocytes have been shown to
rescue proteolysis decits [118].
Restoration of lysosomal acidication as a
therapeutic target
Functional lysosomal V-ATPase and ion channels such as
two-pore channels (TPC) are crucial in maintaining lyso-
somal acidication and function of astrocytes [119]. In
rat astrocytes, activation of TPC by nicotinic acid adenine
dinucleotide phosphate (NAADP) increases autopha-
gosome and lysosome formation [119]. To enhance the
function of lysosomal V-ATPase, C381 is a small-mole-
cule activator of V-ATPase that has been applied to pro-
mote lysosomal acidication in microglia [120], although
its eect in astrocytes remains to be tested. OSI-027 and
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Page 9 of 15
Zeng et al. Journal of Neuroinammation (2025) 22:72
PP242 are two other small-molecular mTOR inhibitors
that have been identied by high-throughput screening
using a uorescent protein based lysosomal pH biosen-
sor [121]. OSI-027 and PP242 were identied as the top
lysosome-acidifying hits in human iPSC-derived astro-
cytes which demonstrated increased lysosomal cathepsin
activity and improved autophagic function [121]. In pri-
mary astrocytes under exposure to environmental toxins,
lysosomal acidication and autophagic ux are impaired
and can be restored by PP242 treatment [122]. Recent
developments using lysosomal-acidifying nanoparticles
to target and restore acidication of impaired lysosomes
have been demonstrated in astrocytes [23, 24]. e intro-
duction of lysosomal-acidifying nanoparticles to mouse
primary astrocytes has led to increased lysosomal acidi-
cation which increased the lysosomal cathepsin activity
and astrocytic phagocytosis of cell debris [23, 24]. Other
types of lysosomal-acidifying nanoparticles have also
been developed [123–125] to re-acidify impaired lyso-
somes and promote autophagic degradation, and this has
been reviewed elsewhere [126–128].
Another approach to promote lysosomal acidication
is through increasing cyclic adenosine monophosphate
(cAMP) levels [129]. Balomycin A1 treatment to astro-
cytes induced dysfunctional V-ATPase and lysosomal
alkalization, while increasing cAMP levels via activation
of PKA signaling pathway restored lysosomal acidica-
tion [130]. Treatment with cilostazol, a phosphodies-
terase inhibitor that inhibits the degradation of cAMP,
reacidies lysosomes in astrocytes, thereby increasing
Aβ degradation in astrocytes [131]. In addition, while
the acute treatment of cAMP activates the AKT survival
pathway in astrocytes, chronic exposure of cAMP has
been observed to activate the FoxO-mediated Bim/Bax
death pathway [132]. erefore, the reliance on cAMP
elevation to acidify lysosomes requires dosage optimiza-
tion, as high cAMP level is observed to exacerbate the
vulnerability of astrocytes to oxidative stress [132, 133].
Interestingly, pharmacological inhibitors and siRNAs
of H+/K+-ATPase elevated lysosomal pH in balomycin
A1 and cAMP co-treated astrocytes, suggesting that H+/
K+-ATPase may function as an alternative proton pump
for lysosomes when the V-ATPase function is impaired
[130]. Hence, pharmacological agents that target the H+/
K+-ATPase may be a new avenue for lysosome-acidifying
therapeutics. Other molecular targets to restore lyso-
somal pH and autophagic function have been explored.
An important therapeutic target is TFEB, where its
expression regulates lysosome biogenesis and expression
of V-ATPase, thereby maintaining lysosomal acidication
[107, 134]. Stereotaxic injection of adeno-associated viral
particles carrying TFEB driven by a glial brillary acidic
protein (GFAP) promoter was used to achieve astrocyte-
specic expression of the gene in the hippocampus of
APP/PS1 transgenic mice. Expression of TFEB in these
astrocytes enhanced lysosome function, resulting in
reduced Aβ plaques in the hippocampus [95]. Aspirin has
also been shown to upregulate TFEB and increases lyso-
somal biogenesis in mouse astrocytes through inducing
the activation of PPARα and stimulated the transcrip-
tion of TFEB [135]. Furthermore, progranulin may also
be a promising target as it mediates TFEB expression [95,
136]. However, careful regulation of TFEB expression is
essential, as excessive activation could lead to potential
side eects, including its role as an oncogenic regulatory
marker [137, 138].
Summary and future perspectives
Astrocytes play a critical role in maintaining energy
metabolism and neuronal health in the CNS [4, 139].
e eectiveness of autophagic and phagocytic func-
tions by astrocytes depends on the extent of lysosomal
acidication and degradation (Fig.4A). Pathogenic fac-
tors, including neuroinammatory signaling, metabolic
stressors, and the accumulation of lipids and toxic pro-
tein aggregates, contribute to the impairment of astro-
cytic lysosomal acidication, resulting in dysfunctional
autophagy and phagocytosis. However, it remains unclear
whether these pathogenic factors directly drive lysosomal
dysfunction in astrocytes or if the defects are secondary
eects of astrocyte reactivity induced by these stress-
ors, neither is mutually exclusive. Further studies are
required to disentangle these mechanisms and clarify the
causal relationships underlying astrocytic dysfunction.
Due to the crosstalk between mitochondria and lyso-
some [140], it is important to investigate how restoration
of mitochondria function, metabolic activity, and lipid
metabolism in astrocytes might oer potential avenues
to maintain optimal lysosomal acidication and eective
degradation.
e generation of the mRFP-eGFP-LC3 mouse model,
which is designed to monitor changes in autophagic ux
due to alterations in lysosomal acidication [141], with a
astrocyte promoter such as GFAP will enable the exami-
nation of the eects of lysosomal acidication impair-
ment in astrocytes in vivo. We also discussed molecular
targets and potential therapeutics that regulate lysosomal
pH, including small molecules and lysosome-targeting
nanoparticles. It is essential to further investigate how
these therapeutics modulate lysosomal acidication and
overall cellular function under dierent disease condi-
tions and reactivity states of astrocytes. Furthermore,
proling of astrocyte heterogeneity using omics charac-
terizations will reveal cellular subtypes that are directly
implicated by lysosomal acidication dysfunction and
enable the elucidation of new molecular targets for bet-
ter and more eective intervention [32, 142–145]. While
this review focuses on targeting lysosomal acidication
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Zeng et al. Journal of Neuroinammation (2025) 22:72
in astrocytes, it is important to note that lysosomal dys-
function also occurs in other CNS cell types, such as
microglia and neurons, under pathological conditions
[127, 128, 146]. In addition to defects in lysosomal acidi-
cation, lysosomal enzyme deciencies play a critical role
in maintaining astrocytic function, as well as the function
of other CNS cell types [147–149]. In infantile neuronal
ceroid lipofuscinosis (CLN1 disease), primary cultures
of astrocytes, microglia, and neurons derived from
Ppt1-decient mice exhibit impaired cellular function.
Ppt1-decient astrocytes display dysregulated calcium
signaling, resulting in increased cell death. In co-culture
experiments, the presence of both Ppt1-decient astro-
cytes and microglia further disrupted the morphology
of both wild-type and Ppt1-decient neurons [150], sug-
gesting that the astrocytes be cross primed by impaired
microglia to become neurotoxic under disease condi-
tions [150, 151]. Given the interconnected roles of these
cells, a broader therapeutic approach targeting lysosomal
function across multiple CNS cell types may oer more
comprehensive benets, highlighting the need to assess
the extent and specic cellular contributions of lysosomal
impairments.
e supportive functions of astrocytes have recently
been extended to them taking on a more active role as
phagocytes similar to microglia. ese functions include
the phagocytosis of cellular debris, synapse elimination,
and the regulation of neuronal activity [8, 152]. Com-
parative studies suggest that astrocytes complement the
phagocytic activity of microglia, although their mecha-
nisms of action are distinct [8, 152]. Astrocytic activity-
dependent synaptic pruning requires the involvement
of phagocytic receptors multiple EGF-like-domains 10
(MEGF10) and MER Tyrosine Kinase (MERTK), both
of which are highly expressed in developing astrocytes
[153]. Subsequent studies have highlighted the critical
role of MEGF10 in synaptic pruning within adult mice,
where astrocytes eliminate excitatory synapses in the
hippocampus to maintain circuit homeostasis and sup-
port memory formation [154]. In contrast, microglia-
mediated synapse elimination involves activation of the
classical complement pathway [155–157]. Specically,
the complement cascade initiator, C1q, localizes to devel-
oping synapses, marking them for microglial phagocy-
tosis in a complement component 3-dependent manner
[155]. A recent study illustrates that the lysosomal pH
Fig. 4 Astrocyte-microglia interactions to promote clearance of unwanted and toxic materials in the cells. (A) Under normal conditions where the un-
wanted materials are within the clearance capacity of astrocytes, phagocytic/autophagic degradation of the accumulated materials can proceed. During
chronic exposure to these unwanted materials, lysosomal functions are impaired, and this reduces the capacity of astrocytes to degrade, leading to the
accumulation of toxic materials within the astrocytes and their subsequent dysfunction. (B) Astrocytes-microglia crosstalk through tunneling nanotubes
(TNTs). In astrocyte-microglia interaction, unwanted and toxic cellular materials such as impaired lysosomes, undegraded autophagosomes, and dam-
aged mitochondria can migrate to microglia, where the latter can assist in more eective degradation of these toxic products. The gure was created
with BioRender.com
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Page 11 of 15
Zeng et al. Journal of Neuroinammation (2025) 22:72
of astrocytes is lower than that of microglia and astro-
cytes are more resistant to alterations in lysosomal pH
compared to microglia [158]. Despite being more acidic,
another study has shown that astrocytes phagocytose
less Aβ than microglia in cell culture and rat brain slices
[159]. In the presence of dying cells, astrocytes appear
to degrade most cells at proximity without the need for
constant cell migration, while microglia are sparse and
require constant movement to detect and engage dying
cells. is suggests that astrocytic phagocytosis would
be more energetically favorable than microglia [160]. A
similar study in the degradation of toxic materials like
Aβ show a complementary feedback between microglia
and astrocytes to remove the aggregate [161]. Further-
more, there is evidence to suggest that astrocytes can
potentially exchange materials with microglia through
tunneling nanotubes (Fig.4B), which may promote more
ecient phagocytosis, although the exact mechanism
remains to be investigated [162–164].
An important future direction of study would be to
document crosstalk between microglia and astrocytes,
which would provide more detailed understanding and
insights into the overall phagocytic processes [165,
166]. is new appreciation for the phagocytic function
of astrocytes complements the basal autophagy func-
tions of astrocytes to contribute to neurodegenerative
and neuroprotective mechanisms in the CNS. is shifts
the current treatment paradigm to consider restoration
of lysosomal acidication and degradative functions in
astrocytes as a therapeutic target for neurodegenera-
tive diseases [24, 95]. Astrocytes and microglia may have
cooperative or opposing interactions during phagocyto-
sis as well as further interactions with neurons [167, 168].
e extent of which they target specic synapses or toxic
proteins and how they work together in dierent circum-
stances requires further investigation. ere is also inter-
action between astrocytes and endothelial cells through
microRNA that targets V-ATPase and modulates lyso-
somal acidication which can determine the level of
endothelial adhesion molecules and the extent of neutro-
phil migration through the BBB [169]. It is important to
comprehend these interactions and their eects on brain
homeostasis under both healthy and diseased conditions,
as this knowledge is crucial for developing treatments for
neurological disorders.
Acknowledgements
The authors thank the funding sources for supporting this work.
Author contributions
C.H.L. conceived the review topic. J.Z., J.I., and C.H.L. wrote the manuscript
and prepared the gures. D.P. provided critical comments and edited the
manuscript.
Funding
C.H.L. is supported by a start-up grant from the Department of Biology at
Syracuse University. J.Z. is supported by a start-up grant from the Department
of Biomedical and Chemical Engineering at Syracuse University.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
All authors have approved the nal version of the manuscript.
Competing interests
The authors declare no competing interests.
Received: 2 May 2024 / Accepted: 5 March 2025
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