# Mitochondria modulate Tau pathology and neuroinflammation

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $595,891

## Abstract

Project Summary
Mitochondrial dysfunction and synaptic damage are early pathological features of the Alzheimer's disease (AD)-
affected brain. Microtubule associated protein tau (MAPT) plays a major role in AD and have deleterious effects
on mitochondrial and synaptic function. Accumulation of abnormal Tau, including Tau oligomers, causes
mitochondrial and synaptic damage, inflammation, and memory impairment. The underlying mechanisms of
abnormal Tau accumulation and strategies to eliminate them to restore mitochondrial function remain largely
unknown. Cyclophilin D (CypD) is an integral part in the formation of the mitochondrial permeability transition
pore (mPTP), leading to cell death. Loss of CypD protects against Aβ-induced mitochondrial and synaptic injury.
However, the role of CypD in tau-mediated mitochondrial and Tau pathology has not been explored. In our
preliminary studies, we found that CypD specifically interacts with tau in AD brains and Tauopathy model. Loss
of CypD robustly reduced hyperphosphorylated Tau and Tau oligomers and restored mitochondrial and cognitive
function in human mutant Tau mice. Furthermore, CypD-deficient Tau mice revealed suppression of induction of
proinflammatory mediators. These exciting results lead us to hypothesize that CypD-mediated mitochondrial
dysfunction provokes neuroinflammation, contributing to abnormal tau metabolism and clearance. To test this
hypothesis, we will investigate whether blockade of CypD promotes abnormal tau clearance consequently
reducing tauopathy and thereby alleviating tau-induced aberrant mitochondrial and cognitive decline in AD.
Utilizing novel genetically manipulated CypD-AD mouse models and neuronal culture with altered CypD levels
in tau-rich environment, and AD cybrids containing patient AD-derived mitochondria, we will elucidate CypD-
dependent mechanisms underlying Tau pathology, clearance, mitochondrial alterations, and neuroinflammation.

## Key facts

- **NIH application ID:** 10263269
- **Project number:** 5R01AG069426-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Shirley ShiDu Yan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $595,891
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10263269

## Citation

> US National Institutes of Health, RePORTER application 10263269, Mitochondria modulate Tau pathology and neuroinflammation (5R01AG069426-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10263269. Licensed CC0.

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