# Role of T cells in tau-mediated neurodegeneration

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $750,628

## Abstract

Alzheimer’s disease (AD) and primary tauopathies are disorders in which the aggregation and accumulation of
tau plays a key role in pathogenesis. In AD, tau aggregation and accumulation begins in the medial temporal
lobe and extends into several neocortical regions just as cognitive decline begins and its progressive
accumulation significantly correlates with neuronal/synaptic loss, regional brain atrophy, and
neurodegeneration. Importantly, the regional presence and progression of brain atrophy and functional decline
in both primary tauopathies and in AD highly correlates with tau accumulation. We have produced mice that
develop tau pathology and tau-mediated neurodegeneration that are crossed onto a human APOE knockin (KI)
background (P301S tau transgenic mice that express human APOE isoforms). We found that tau-mediated
neurodegeneration is dependent on the presence of APOE with APOE4 resulting in greater damage than other
APOE isoforms. The tau-linked neurodegeneration also requires microglia. While the tau-associated damage is
dependent on the brain’s innate immune response via microglia, little is known about the extent and role of the
adaptive immune responses in the presence of amyloid-β (Aβ) or tau pathology. Importantly, the contribution of
the adaptive immune response to tau-mediated neurodegeneration has been unclear. We recently compared
the immunological milieus in the brain of mice with amyloid deposition or tau aggregation and
neurodegeneration. We found that mice with tauopathy but not amyloid, developed a unique innate and
adaptive immune response and that depletion of microglia or T cells strongly attenuated tau-mediated
neurodegeneration. Both CD4 and CD8 T cells were markedly increased in areas with tau pathology in P301S
mice and in the AD brain. T cell numbers correlated with the extent of neuronal loss, and dynamically
transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal
expansion. Inhibition of molecules either secreted by T cells (IFN-γ) or present on the surface of some T cells
(PD-1) both significantly ameliorated brain atrophy. Our results have revealed a tauopathy and
neurodegeneration-related immune hub involving activated microglia and T cell responses. Given these data,
we hypothesize that understanding the role and interactions of T cells, microglia, and antigen presenting cells
in tau-mediated neurodegeneration will provide novel insights into the tau-mediated pathogenesis as well as
provide new therapeutic targets for preventing neurodegeneration in AD and primary tauopathies. This
hypothesis will be tested in 3 Aims. Aim 1 will investigate the mechanisms underlying T cell activation and role
of effector functions in microglia and T cells in tau-dependent neurodegeneration. Aim 2 will investigate
potential antigen T cell receptor interactions that are relevant to T cell activation in P301S Tau Tg mice. Aim 3
will test whether different classes of clinically-...

## Key facts

- **NIH application ID:** 10805729
- **Project number:** 1R01AG085374-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** DAVID M. HOLTZMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $750,628
- **Award type:** 1
- **Project period:** 2024-02-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10805729

## Citation

> US National Institutes of Health, RePORTER application 10805729, Role of T cells in tau-mediated neurodegeneration (1R01AG085374-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10805729. Licensed CC0.

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