# Mitochondrial modulation of neuroinflammation in AD and related tauopathies

> **NIH NIH RF1** · UNIVERSITY OF ARIZONA · 2020 · $1,568,250

## Abstract

Project Summary
Alzheimer's disease (AD) is the most common dementia in the elderly characterized by neurofibrillary tangles,
senile plaques and a progressive loss of brain neurons. Compared with senile plaques, neurofibrillary tangles
have a better correlation with the severity of cognitive impairment in AD. As intracellular lesions, neurofibrillary
are largely composed of hyperphosphorylated microtubule-associated protein tau. Not surprisingly, considerable
efforts have been devoted to tau-based AD drug development though the pathomechanism underlying tau
toxicity remains largely unknown. Mitochondrial dysfunction and neuroinflammation are prominent early
pathological features of AD and have been increasingly implicated as critical factors for AD pathogenesis.
Despite both mitochondrial dysfunction and neuroinflammation have been repeatedly reported in animal models
of tauopathies, there is limited study of their interplay. Interestingly, in our preliminary studies, we found that
Mfn2, the mitochondrial outer membrane protein regulating mitochondrial morphology and association with
endoplasmic reticulum, was significantly reduced in the widely used PS19 tau transgenic mice for AD and related
tauopathies. Excitingly, the overexpression of Mfn2 in neurons is sufficient to remarkably suppress tau
phosphorylation, mitochondrial dysfunction, neuroinflammation, neuronal loss and behavioral deficits in PS19
mice. In addition, lipopolysaccharide-induced neuroinflammation and even sudden death could also be greatly
suppressed by overexpressing Mfn2 in neurons, together implying neuronal Mfn2 as a crucial mediator for both
mitochondrial dysfunction and neuroinflammation. These exciting and promising preliminary studies suggest that
a detailed investigation into the potential role of Mfn2 as a point of convergence for mitochondrial dysfunction
and neuroinflammation in AD and related tauopathies is warranted. Using novel transgenic mouse models and
a promising synthetic therapeutic peptide inhibiting Mfn2 degradation, this study will not only study whether and
how Mfn2 regulates mitochondrial dysfunction and neuroinflammation, but also test the feasibility of targeting
Mfn2 as a novel therapeutic approach against tau toxicity. Tau pathology is a prominent common
histopathological feature of various major neurodegenerative diseases including but not limited to AD. Our
proposed studies of Mfn2 and its convergent role in mitochondrial dysfunction and neuroinflammation will have
very broad scientific and translational significance.

## Key facts

- **NIH application ID:** 10766083
- **Project number:** 7RF1AG065342-03
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Xinglong Wang
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,568,250
- **Award type:** 7
- **Project period:** 2020-09-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10766083

## Citation

> US National Institutes of Health, RePORTER application 10766083, Mitochondrial modulation of neuroinflammation in AD and related tauopathies (7RF1AG065342-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10766083. Licensed CC0.

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