# Mechanisms of Presynaptic Energetic Failure Due to Age-Related Pathologic Tau Accumulation

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $381,250

## Abstract

Abstract:
 Aging is the greatest risk factor for the development of the debilitating neurodegenerative disorder
Alzheimer's disease (AD). Histopathologically, AD is characterized by the accumulation of extracellular amyloid
plaques and intracellular neurofibrillary tangles (consisting of hyperphosphorylated and aggregated tau) in the
brain, which are accompanied by dramatic synaptic and neuronal loss. Deposition of abnormally
phosphorylated tau is also common in the normal aging brain. Despite evidence that pathologic tau
accumulation and synaptic alterations correlate with cognitive deficits in AD patients, the mechanism(s)
underlying such alterations remain incompletely characterized. Growing evidence points to disturbances in
mitochondrial and synaptic function; processes also affected by normal aging. Our preliminary data suggest
that pathologic tau accumulates within nerve terminals and associates with presynaptic mitochondria from
hTau mice in an age-dependent manner, resulting in development of an aged metabolic phenotype, namely
alterations of presynaptic mitochondrial parameters and impairment of spare respiratory capacity in nerve
terminals, suggesting neuronal synapses may be particularly vulnerable to both aging- and pathologic tau-
induced mitochondrial dysfunction.
 Specific Aim 1 will determine how pathologic tau accumulation contributes to presynaptic mitochondrial
functional and proteomic alterations, and Specific Aim 2 will examine how pathologic tau accumulation
contributes to presynaptic mitochondrial DNA damage, associated with normal aging. Specific Aim 3 will
assess Parkin function as a target to ameliorate the presynaptic mitochondrial dysfunction associated with
pathologic tau accumulation. Innovative aspects include our mechanistic studies to identify possible new
targets for AD based on overlapping changes that we observe with normal brain aging and in the context of tau
pathology, specifically, alterations in presynaptic mitochondrial function. These R01 studies will help bridge this
gap in our knowledge and lead to future studies to identify strategies to alleviate such mechanisms(s) of
disease pathogenesis.

## Key facts

- **NIH application ID:** 10434003
- **Project number:** 5R01AG059785-05
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Kelly Lynn Stauch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2018-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434003

## Citation

> US National Institutes of Health, RePORTER application 10434003, Mechanisms of Presynaptic Energetic Failure Due to Age-Related Pathologic Tau Accumulation (5R01AG059785-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10434003. Licensed CC0.

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