Vai trò mới nổi của hệ miễn dịch bẩm sinh và thích ứng trong bệnh Tauopathies

Review

Emerging roles for innate

and adaptive immunity in tauopathies

Alexis M. Johnson

1,2,3,4

and John R. Lukens

1,2,3,4,

Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA

Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA

Brain Immunology and Glia Graduate Training Program, University of Virginia, Charlottesville, VA 22908, USA

Harrison Family Translational Research Center in Alzheimer’s and Neurodegenerative Diseases, University of Virginia, Charlottesville, VA

22903, USA

*Correspondence: jrl7n@virginia.edu

https://doi.org/10.1016/j.celrep.2025.116232

SUMMARY

Tauopathies encompass a large majority of dementia diagnoses and are characterized by toxic neuronal or

glial inclusions of the microtubule-associated protein tau. Tau has a high propensity to induce prion-like

spreading throughout the brain via a variety of mechanisms, making tauopathy a rapid and lethal form of neu-

rodegeneration that currently lacks an effective therapy or cure. Tau aggregation and neuronal loss associ-

ated with this pathology are accompanied by robust neuroinflammation. Innate immune responses—partic-

ularly those involving microglial activation, altered lipid metabolism, and type I interferon signaling—have

emerged as key drivers of tau hyperphosphorylation and aggregation. Recent advances also point to a sig-

nificant role for the adaptive immune system in shaping tauopathy progression. This review examines the cur-

rent understanding of innate immunity in tauopathies and highlights emerging evidence linking T cell re-

sponses to tauopathy progression. Last, we conclude with a discussion of potential ways in which the

immune system can be harnessed to treat tauopathy.

INTRODUCTION

Tauopathies are a class of neurodegenerative diseases charac-

terized by the abnormal intracellular accumulation of tau protein.

These include Alzheimer’s disease (AD), frontotemporal demen-

tia (FTD), progressive supranuclear palsy, corticobasal degener-

ation, chronic traumatic encephalopathy, and others. In these

diseases, tau aggregates act in a prion-like fashion, spreading

across brain regions and driving neurodegeneration.

Regarding

homeostatic function, tau exists as a microtubule-associated

protein that aids in the maintenance of neuronal architecture

and intracellular transport. However, under cellular stress,

inflammation, or dysregulated signaling conditions, tau un-

dergoes post-translational modifications, such as phosphoryla-

tion and acetylation. Excessive post-translational modifications

of tau result in its misfolding and aggregation into oligomers, fil-

aments, and tangles.

These aggregated tau species disrupt

neuronal function and viability, ultimately contributing to subse-

quent cognitive decline and brain atrophy.

While the pathological role of tau has been well studied, the

contribution of the immune system to tau-mediated neurode-

generation is gaining traction as a pivotal driver of disease.

Once thought to be immune privileged, the central nervous sys-

tem (CNS) is now understood to host dynamic immune activity

through resident macrophages, such as microglia, and interac-

tions with peripheral immune cells.

Unchecked inflammation

is well established as detrimental to neuronal health, and a

growing body of work has begun to reveal the molecular mech-

anisms by which immune activation contributes to tau pathol-

ogy. This review aims to synthesize current findings on how

innate and adaptive immune responses shape tau-driven neuro-

degeneration and highlight emerging therapeutic opportunities

to target these immunological mechanisms.

Innate immune responses that influence tauopathies

The innate immune system serves as the body’s first line of de-

fense against infection and cellular damage. Unlike the adaptive

immune system, which mounts specific responses tailored to in-

dividual antigens, innate immunity relies on evolutionarily

conserved receptors to rapidly detect general danger signals,

such as microbial components or signs of cellular stress. In the

CNS, microglia are the primary innate immune cells and play

key roles in maintaining tissue homeostasis. These cells are

equipped with pattern recognition receptors (PRRs), including

Toll-like receptors (TLRs) and inflammasomes, which initiate in-

flammatory signaling cascades.

While these responses are

essential for protecting the brain from acute challenges, persis-

tent or dysregulated innate immune activation can lead to

chronic neuroinflammation and contribute to neurodegenerative

disease.

In the context of tauopathies, growing evidence implicates

several innate immune pathways as key drivers of disease

onset and progression. Among the most studied are comple-

ment signaling, TLR activation, and inflammasome-mediated

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

OPEN ACCESS

responses, all of which have been shown to promote inflamma-

tory environments that exacerbate tau pathology (Figures 1A–

1C). Emerging data also suggest that innate immune-based

DNA damage-sensing pathways, such as the cGAS-STING

axis and its regulation of downstream interferon (IFN) responses,

are involved in amplifying neuroinflammation in tau-mediated

neurodegeneration (Figure 1D). Additionally, recent findings indi-

cate that disrupted immunometabolism and lipid processing

within innate immune cells may further fuel pathogenic inflam-

matory responses in primary tauopathies (Figure 1E). In the sec-

tions that follow, we explore these mechanisms in greater detail

and highlight how innate immune dysregulation intersects with

tau pathology.

Complement cascade

The complement system is a proteolytic cascade that plays a

central role in immune defense by tagging, opsonizing, and

lysing cellular threats. All three complement activation path-

ways—classical, lectin, and alternative—converge at the forma-

tion of C3 convertase, ultimately leading to the assembly of the

A B C D E

Figure 1. Contributions of the innate immune system to tauopathy progression

Shown is the immunological interface between a microglial cell (red) and a neuron (gray), highlighting five key innate immune pathways implicated in the response

to extracellular tau fibrils and aggregates.

(A) Tau-burdened synapses are tagged with complement proteins such as C1q, which promotes microglial synaptic engulfment, which exacerbates pathology.

Soluble C3a (yellow half-circles) promotes an inflammatory environment and worsens tauopathy when bound to C3aR. Extracellular tau fibrils interact with CR4

and can be internalized in a neuroprotective fashion.

(B) Tau aggregates can trigger NLRP3 inflammasome assembly in microglia, leading to the activation of caspase-1, cleavage of gasdermin D (GSDMD), and

release of the pro-inflammatory cytokines (blue spheres) IL-1β and IL-18. These cytokines can propagate neuroinflammation and contribute to tau pathology in a

context-dependent manner.

(C) Detection of tau by TLRs expressed on neurons and microglia incites proinflammatory cytokine production and further tau hyperphosphorylation and ag-

gregation.

(D) cGAS detects cytosolic DNA and activates STING, resulting in type I IFN production and the induction of IFN-stimulated genes (ISGs) via IFNAR in neurons and

microglia. This cascade inhibits transcription factors like MEF2C, thus promoting microgliosis and inflammatory responses that worsen tauopathy.

(E) Tauopathy-driven lipid droplet accumulation leads to defective microglial phagocytosis and excessive production of proinflammatory cytokines and reactive

oxygen species (ROS). Apolipoprotein E4 (APOE4) exacerbates these effects in neurons and microglia, leading to heightened inflammatory responses and

worsened tau pathology.

2 Cell Reports 44, September 23, 2025

Review

OPEN ACCESS

membrane attack complex, which can directly lyse target cells.

In addition to its cytolytic function, complement activation also

facilitates opsonization and promotes immune cell recruitment

via the generation of chemoattractant fragments such as C3a

and C5a.

In the CNS, microglia and astrocytes serve as both

key sources and targets of complement proteins. While cerebral

complement signaling was once thought to be primarily acti-

vated in response to infection and injury, it is now recognized

as a dynamic regulator of brain homeostasis as well as sterile

pathological processes.

For instance, during development,

complement components such as C1q and C3 facilitate the elim-

ination of excess synapses.

9,10

This is a critical pruning mecha-

nism that, when dysregulated, contributes to synaptic loss in

neurodegenerative diseases.

10,11

In tauopathies, dysregulated complement activity is increas-

ingly recognized as a hallmark of disease pathology. Elevated

expression of C1q, a key initiator of the classical complement

cascade, has been observed in both symptomatic and presymp-

tomatic individuals with tauopathies as well as in multiple tauop-

athy mouse models. This suggests that complement activation

may precede overt neurodegeneration and contribute to disease

progression (Figure 1A).

12,13

Genetic deletion of C1q in the PS19

mouse model of tauopathy has been shown to attenuate syn-

apse loss and neurodegeneration, supporting a pathological

role for this complement molecule in FTD.

However, it should

be noted that follow-up investigation by the same group added

nuance to the notion that C1q inhibition is uniformly beneficial.

Here, they showed that, although chronic deletion provided pro-

tective effects, acute treatment with C1q-blocking antibodies

failed to restore synaptic function or prevent neuronal loss

even when administered at early symptomatic stages

(Figure 1A).

14,15

These conflicting results suggest that timing,

disease stage, and therapeutic strategy (i.e., genetic vs. pharma-

cologic) may critically influence disease outcomes when target-

ing C1q in tauopathy. Moreover, these findings highlight the

nuanced role of complement in tauopathy and the challenges

of developing effective therapies targeting this pathway.

In addition to C1q, C3 signaling has also emerged as a central

contributor to tau pathology. Genetic deletion of C3 or its receptor

C3aR has been shown to reduce neuroinflammation and amelio-

rate neurodegenerative phenotypes in tauopathy models.

Furthermore, in vitro studies have identified the complement re-

ceptor CR4 on microglia as a receptor for tau fibrils, mediating

their internalization and potentially linking complement signaling

to tau clearance mechanisms (Figure 1A).

Despite these in-

sights, direct in vivo evidence for CR4-mediated tau clearance re-

mains absent. Therefore, future studies are needed to evaluate

whether CR4-targeting strategies can enhance tau removal and

protect neuronal function in tauopathy models.

Inflammasome signaling

Inflammasomes are multiprotein signaling complexes that coor-

dinate the production of the proinflammatory cytokines inter-

leukin-1β (IL-1β) and IL-18, and also execute a gasdermin

D (GSDMD)-driven form of cell death known as pyroptosis. In-

flammasomes typically consist of an innate immune sensor

molecule such as NLRP3 or AIM2, the adaptor protein ASC,

and caspase-1. Formation of this signaling platform positions

caspase-1 in the correct orientation to allow for its auto-cleavage

and subsequent activation. Canonical inflammasome activation

follows a two-step process: a priming signal, typically via nuclear

factor κB (NF-κB) activation, which induces the expression of in-

flammasome components (e.g., NLRP3) and pro-cytokines. The

secondary signal, often triggered by pathogen- or damage-

associated molecular patterns (PAMPs or DAMPs, respectively),

activates the inflammasome sensor, which instructs complex as-

sembly and cleavage-induced caspase-1 activation.

Once

activated, caspase-1 then proceeds to cleave pro-IL-1β, pro-

IL-18, and full-length GSDMD, which elicits their biological acti-

vation. In the context of tauopathies, internalization of patholog-

ically phosphorylated tau (p-tau) by microglia has been shown to

trigger NLRP3 inflammasome activation.

Once released, IL-1β and IL-18 amplify inflammatory signaling

cascades that can indirectly promote further tau pathology. Spe-

cifically, these cytokines activate their respective receptors on glia

and neurons, leading to downstream signaling through the MAPK

(mitogen-activated protein kinase) and JNK (c-Jun N-terminal ki-

nase) pathways, both of which are known to hyperphosphorylate

tau. Indeed, in vitro studies indicate that IL-1β and IL-18 can upre-

gulate the activity of several tau kinases, including GSK3β, CDK5,

and p38 MAPK (Figure 1B).

21–24

Furthermore, elevated in vivo

expression of IL-1β in tauopathy mouse models has been associ-

ated with increased kinase activity and exacerbated tau hyper-

phosphorylation,

which suggests a feedforward loop that links

inflammasome activation with progressive tau pathology.

Earlier studies using tauopathy mouse models (i.e., PS19 and

Thy-Tau22 mice) found that genetic deletion of inflammasome

components such as Nlrp3 or Asc reduced tau aggregation

and improved cognitive outcomes (Figure 1B).

26–28

These find-

ings support a model in which inflammasome activation in micro-

glia contributes to tau pathology, likely through the production of

proinflammatory cytokines (e.g., IL-1β). Conversely, more recent

work using the Thy1-hTau.P301S model, which exhibits a

different regional pattern of tau pathology, did not observe

appreciable changes in disease progression or cytokine levels

following genetic deletion of Nlrp3 or Gsdmd in microglia

(Figure 1B).

These conflicting results suggest that inflamma-

some-mediated pathology in tauopathies may be context

dependent. Most notably, differences in the discrete tauopathy

mouse models employed in these studies could help to explain

these divergent results. More specifically, differences in pro-

moter systems (e.g., Prnp in PS19 vs. Thy1 in hTau.P301S),

tau isoforms expressed (e.g., hTau mice expressing all six iso-

forms vs. 0N4R in Thy1-hTau.P301S), and regional vulnerability

(hippocampal vs. midbrain) may all influence the overall impact

inflammasome deletion has on tauopathy disease progression.

Nevertheless, future studies are needed to further reconcile

these disparate results regarding the involvement of inflamma-

some signaling in tauopathies. Further efforts to decipher the

optimal targeting of inflammasome signaling in tauopathies will

lead to improved understanding of disease etiology and the

development of more effective treatment strategies.

TLR signaling

TLRs are PRRs that detect DAMPs and PAMPs, initiating immune

responses via NF-κB, MAPK, and IFN signaling.

In tauopathies,

Cell Reports 44, September 23, 2025 3

Review

OPEN ACCESS

TLR activation promotes neuroinflammation and exacerbates tau

pathology by upregulating tau kinases such as CDK5, MAPK,

GSK3β, and JNK, ultimately driving tau hyperphosphorylation

and aggregation (Figure 1C). Indeed, in vitro studies using SH-

SY5Y neuroblastoma cells demonstrated that TLR3 stimulation

leads to enhanced phosphorylation of tau through downstream

signaling cascades, implicating TLR3 in the modulation of tau ki-

nases.

Likewise, TLR9 activation induced by stimulating primary

hippocampal neurons under high-glucose conditions was simi-

larly shown to promote hyperphosphorylation of tau.

Later

research extended these findings by showing that extracellular

pathogenic tau can directly activate TLR4-dependent inflamma-

tory cascades, further amplifying neuroinflammation and tauop-

athy progression in vivo (Figure 1C).

These studies underscore

the relevance of distinct TLR pathways in promoting pathological

tau modifications through kinase activation.

To add further complexity to the innate immune responses dis-

cussed thus far, complement, TLR, and inflammasome path-

ways do not act in isolation but form an interconnected network

that amplifies neuroinflammation and tau pathology. For

instance, TLR4 activation by extracellular tau can prime inflam-

masome components and promote the release of IL-1β and IL-

18,

which, in turn, upregulate tau kinases such as GSK3β

and CDK5 in neurons.

21–25

In parallel, IL-1β and complement-

mediated signaling increase neuronal oxidative stress, leading

to neuronal phosphatidylserine exposure and phagoptosis by

microglia, another point of convergence between TLR and in-

flammasome pathways.

33–35

Complement receptor CR4 also fa-

cilitates microglial uptake of tau fibrils, potentially acting in con-

cert with TLR-driven responses.

Despite these emerging links,

the coordination and hierarchy of these interactions remain

poorly understood. Future studies should explore how these

pathways intersect over time and across brain regions and

whether targeting common regulatory nodes, such as NF-κB

signaling or oxidative stress, might yield more effective thera-

peutic strategies than interventions focused on isolated innate

immune pathways.

DNA damage sensing by the innate immune system

Protein aggregates, like tau-based neurofibrillary tangles (NFTs),

are known to induce damage to both the nucleus and mitochon-

dria, which can lead to the subsequent accumulation of mito-

chondrial DNA (mtDNA) and genomic DNA damage as tauopa-

thies progress.

This mislocalization of mtDNA and genomic

DNA into the cytosol can then trigger innate immune DNA-

sensing pathways such as cyclic GMP-AMP synthase (cGAS)

stimulator of interferon genes (STING) and the AIM2 inflamma-

some. These pathways have been increasingly implicated in

many neurological conditions.

However, as the tauopathy field

stands, cGAS-STING is the predominant DNA damage immune

pathway implicated.

cGAS is one of many sensors capable of detecting cyto-

plasmic double-stranded DNA (dsDNA). The source of this

dsDNA can vary, originating from exogenous pathogens, such

as viruses or bacteria, or from endogenous sources, like mtDNA

or genomic DNA damage.

Upon activation, cGAS catalyzes

the production of the second messenger cyclic guanosine

monophosphate-AMP, which then initiates STING activation at

the endoplasmic reticulum. STING activation promotes phos-

phorylation and binding with TANK-binding kinase 1 (TBK1)

and IFN regulatory factor 3, facilitating their nuclear translocation

to IFN response elements and NF-κB target sites. The resulting

transcriptional events enhance type I IFN- and NF-κB-mediated

cytokine production and can promote cell death in some

instances.

During aging, independent of any major pathology, levels of

type I IFNs rise (Figure 2).

Chronic exposure to type I IFN alone

is sufficient to induce cognitive decline and accelerate aging-

related phenotypes in mice.

Within the CNS, microglia are

key responders to IFN signaling, and under prolonged IFN stim-

ulation, they adopt an altered, maladaptive activation state.

compelling illustration of the impact of dysregulated IFN

signaling comes from studies of microglia derived from induced

pluripotent stem cells of individuals with Down syndrome, where

trisomy of type I IFN receptor genes results in hypersensitivity to

IFN. These Down syndrome-derived microglia exhibit excessive

synaptic pruning in brain organoids, a phenotype reversed by

interferon-α/β receptor (IFNAR) knockdown and absent in wild-

type controls.

Recent work further supports this model,

showing that sustained IFN signaling in the aged brain primes mi-

croglia toward a chronic inflammatory phenotype that acceler-

ates neurodegeneration, even without classic proteinopathies.

These findings suggest that type I IFNs disrupt microglial ho-

meostasis and sensitize the CNS environment, lowering the

threshold for harmful immune responses to tau and other patho-

logical stimuli.

Both human tauopathy samples and PS19 mouse models

exhibit upregulated cGAS expression and activity

as well as

notable increases in type I IFN responses.

Genetic deletion

of cGAS or pharmacological inhibition of STING was further

shown to dampen pathological hallmarks of tau-mediated dis-

ease, suggesting that cGAS and STING signaling are drivers of

tauopathy pathogenesis (Figure 1D).

It is important to note

that recent reports also suggest that polyglutamine binding pro-

tein 1 (PQBP1) is another driver of cGAS-STING-mediated neu-

roinflammation in tauopathies. In this scenario, it has been pro-

posed that intracellular tau inclusions can bind PQBP1 and

lead to cGAS-STING activation.

How dysregulated cGAS-STING activation contributes to tau-

opathy progression has not yet been conclusively established;

however, multiple potential mechanisms have been proposed.

As described above, one possibility is that cGAS-STING-medi-

ated induction of type I IFN production is responsible for down-

stream potentiation of neuroinflammation and tauopathy.

Consistent with this idea, genetic ablation of the receptor that

coordinates type I IFN signaling, IFNAR, in P301S tauopathy

mice has been shown to markedly attenuate neuroinflammation

and tau pathology.

One notable downstream consequence of exaggerated type

I IFN responses in tauopathy is the marked suppression of

myocyte enhancer factor 2C (MEF2C), a transcription factor

that plays critical roles in both microglial and neuronal homeo-

stasis (Figure 2). In microglia, MEF2C supports a homeostatic,

anti-inflammatory state by repressing pro-inflammatory

gene expression and promoting functions such as synaptic

maintenance and debris clearance.

38,41

In one study, loss of

4 Cell Reports 44, September 23, 2025

Review

OPEN ACCESS

microglial MEF2C was sufficient to induce inflammatory and

aging-associated phenotypes, independent of underlying

neuropathology. These MEF2C-deficient microglia were also

hyperresponsive to acute inflammatory challenge, such as

lipopolysaccharide injection.

In neurons, MEF2C governs

gene expression essential for differentiation, synaptic matura-

tion, and the maintenance of proper network activity.

Recent

evidence shows that activation of the cGAS-STING pathway

and heightened type I IFN signaling contribute to MEF2C

downregulation in neurons within models of tauopathy

(Figure 1D).

Inhibition or deletion of cGAS or STING restored

MEF2C expression, which was associated with reduced syn-

aptic loss and partial rescue of aberrant neuronal firing

(Figure 2).

These findings indicate that chronic cGAS-STING

signaling disrupts MEF2C-dependent regulatory programs.

This can subsequently lead to exacerbated microglial

dysfunction via loss of immune restraint and impaired

neuronal circuit function through dysregulated transcription.

Lipid metabolism-based modulation of innate immunity

Aging is accompanied by widespread metabolic and immune

changes that contribute to cognitive decline and neurodegener-

ative diseases. As cellular metabolic flexibility declines, disrup-

tions in immunometabolism, particularly in lipid processing and

energy utilization, drive chronic neuroinflammation and neuronal

dysfunction.

47,48

Microglia and astrocytes are especially sensi-

tive to these shifts. Both cell types exhibit alterations in glycol-

ysis, mitochondrial function, and lipid metabolism with age, lead-

ing to lipid droplet accumulation, oxidative stress, and impaired

phagocytic clearance of toxic protein aggregates.

One notable

population, lipid droplet-accumulating microglia, has been iden-

tified in the aging brain and displays dysfunctional innate

Figure 2. DNA damage sensing by the innate immune system amplifies type I IFN signaling and exacerbates tau-mediated neuro-

degeneration

Type I IFN (blue spheres) are elevated in aging and tauopathy brains. (1) Microglia (red) are highly responsive to these signals, resulting in increased ISG

expression and microgliosis. Type I IFN signaling also suppresses the transcription factor MEF2C, which normally restrains microglial activation and supports

neuronal resilience. (2) In neurons (gray), tau aggregates induce mitochondrial and nuclear damage, leading to the cytosolic release of double-stranded DNA

(dsDNA). This DNA is sensed by cGAS, activating the STING pathway and triggering further type I IFN production and MEF2C inhibition. Tau aggregates also