# Mechanism of Pathologic Tau Fibrils Neuron-to-Neuron Transmission and Neuroinflammation in Alzheimer's Disease

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $633,002

## Abstract

Project Summary/Abstract:
Neurofibrillary tangles (NFTs) as a hallmark pathology of Alzheimer's disease (AD) are widely distributed in the
AD brain. The major constituent of NFTs is abnormal tau aggregates filling the intraneuronal and glial cell
body. Emerging evidence indicated that pathologic tau fibrils are capable of triggering a self-propagating
process in neurons and other brain cells that leads to neurodegeneration and neuroinflammation.
Experimental data have shown that intracranial injection of pathologic tau fibrils extracted from AD brains
results in substantial spreading of tau pathology in mouse brains and induces behavioral deficits. However,
therapeutic targets to block this pathologic tau spreading have not been identified. We identified for the first
time that lymphocyte-activation gene 3 (Lag3) is an essential receptor mediating the pathologic α-synuclein
transmission. Our preliminary studies further support that Lag3, as a cell surface receptor, mediates the
transmission of tau fibrils and pathologic tau-induced neuronal and microglial deficits. These results suggest
that Lag3 may serve as a novel target for blocking pathogenic tau spreading for therapeutic development. We
have established two mouse models of pathologic tau spreading with validated neuronal and behavioral
deficits as well as neuroinflammatory response. Of note, our preliminary data suggests that Lag3 protein is
expressed both in neurons and microglia, and depletion of Lag3 can inhibit tau neuronal propagation and
microglial activation. All these results support our central hypothesis that Lag3 is an essential receptor of
pathologic tau in neurons and microglia that mediates tau internalization, transmission and tauopathy. Now, it
is feasible to explore the role of Lag3 in facilitating tau pathogenesis and the therapeutic efficacy of Lag3
targeting via genetic deletion and monoclonal antibodies. Our goals are (1) to define the role of Lag3 in
mediating internalization of pathologic tau and the consequent neuronal and microglial responses involved in
the pathogenesis of AD and other tauopathies, and (2) to develop a clinical translatable strategy to inhibit
Lag3-mediated tau pathogenesis for the treatment of tauopathies. If successful, discoveries from this study will
identify a cell-surface receptor that mediates pathologic tau spreading and serve as a novel therapeutic target
for therapeutic development. This project may also provide novel molecular insights into key mediators of
pathologic tau spreading in neurons and other brain cells. Given the on-going clinical trials using anti-Lag3
antibodies for cancer immunotherapy, discoveries from this project will also facilitate the repurposing of these
anti-Lag3 antibodies for treating AD and other tauopathies.

## Key facts

- **NIH application ID:** 10461946
- **Project number:** 5R01AG073291-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Xiaobo Mao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $633,002
- **Award type:** 5
- **Project period:** 2021-08-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461946

## Citation

> US National Institutes of Health, RePORTER application 10461946, Mechanism of Pathologic Tau Fibrils Neuron-to-Neuron Transmission and Neuroinflammation in Alzheimer's Disease (5R01AG073291-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10461946. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*