# The role of mitochondrial fission in neurodegeneration in the leading environmental cause of Alzheimer's disease

> **NIH NIH F30** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $53,974

## Abstract

Project Summary/Abstract
In the past decade, traumatic brain injury (TBI) has been rising in incidence, and is linked to a 2-4 fold
increase in developing Alzheimer's disease and related dementias later in life1–5. TBI presents as a progressive
neurodegenerative injury characterized by cognitive deficits and neuropsychiatric impairment4,6. Currently,
there are no available treatments to prevent, slow, or reverse the chronic progression of neurodegeneration and
accelerated AD after TBI. In many neurodegenerative conditions, including AD, Parkinson's disease,
Huntington's disease, aberrant mitochondrial fission has been identified as a critical component of
pathogenesis7. It has also been implicated in the acute stages of concussive TBI8–10. The goals of this project are
to characterize the changes in regulation of mitochondrial fission that occur in acute and chronic TBI, and to
determine whether pharmacologically limiting aberrantly high mitochondrial fission after TBI provides a
neuroprotective strategy for TBI and TBI-induced accelerated AD.
To address my goal, I propose the following aims, using an established mouse model of TBI:
 1. Determine how TBI affects expression, modification, and activity of the key mediator of mitochondrial
fission, dynamin-related protein 1 (Drp1). I will measure expression of Drp1 across a comprehensive list
 of brain regions at early and late timepoints after TBI. I will also measure post-translational
 modifications, oligomerization activity, and expression of regulatory proteins of Drp1.
2. Determine how pharmacologic inhibition of mitochondrial fission after acute TBI mitigates pathology
and symptoms at acute and chronic timepoints after TBI. I will administer injured mice with P110, a
 small peptide inhibitor of the key mitochondrial fission protein Drp1 which has already been
 determined to be neuroprotective in TBI, and then investigate pathological changes across an array of
 histological measures, ultrastructural changes via transmission electron microscopy, and bioenergetic
 changes via Seahorse analysis.
3. Determine the efficacy of P110 treatment in mitigating TBI-induced acceleration of Alzheimer's disease.
I will administer P110 to 5xFAD mice following mild TBI, and use behavioral testing to determine
P110's efficacy in reducing accelerated neurocognitive deficits. I will also use histological methods to
monitor changes in plaque deposition as a function of TBI and P110 treatment.
Through completing this project, I will acquire new lab techniques, including behavioral testing,
immunohistochemistry, biochemical assays, and both confocal and electron microscopy. I will also foster
collaboration with researchers in related fields of neurodegeneration, and develop clinical insight into the field
of neurodegeneration. This proposal outlines a rigorous training plan by which I will establish the skills needed
for a successful career as a physician-scientist in the fields of neurodegeneration and neuropsychi...

## Key facts

- **NIH application ID:** 10873247
- **Project number:** 5F30AG076183-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Preethy Sridharan
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 5
- **Project period:** 2022-08-08 → 2026-08-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873247

## Citation

> US National Institutes of Health, RePORTER application 10873247, The role of mitochondrial fission in neurodegeneration in the leading environmental cause of Alzheimer's disease (5F30AG076183-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10873247. Licensed CC0.

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