# Mitochondrial modulation of neuroinflammation in AD and related tauopathies

> **NIH NIH RF1** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $612,364

## 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:** 10375646
- **Project number:** 7RF1AG065342-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Xinglong Wang
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $612,364
- **Award type:** 7
- **Project period:** 2020-09-15 → 2022-10-18

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375646

## Citation

> US National Institutes of Health, RePORTER application 10375646, Mitochondrial modulation of neuroinflammation in AD and related tauopathies (7RF1AG065342-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10375646. Licensed CC0.

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