# Monitoring alterations of proteostasis in aging and Alzheimer's disease

> **NIH NIH F31** · UNIVERSITY OF WASHINGTON · 2021 · $40,805

## Abstract

Project Summary/Abstract
 Aging, Alzheimer’s disease (AD), and other neurodegenerative diseases have altered or impaired
proteostasis. In healthy cells, proteostasis involves mechanisms for the stabilization of correctly folded proteins
and the degradation of misfolded or damaged proteins. This balance maintains proteins in a specific
conformation, concentration, and location to be functional, and the coordinated mechanisms prevent the
accumulation of damaged proteins while permitting the continuous renewal of intracellular proteins. In aging,
Alzheimer’s disease, and other neurodegenerative diseases, misfolded proteins aggregate into inclusions,
which indicate that disruption of proteostasis has occurred. Effort has been put into determining what
comprises the inclusions, but the cause of this altered or impaired proteostasis has never been determined. To
improve our understanding of the causes of impaired proteostasis, we will examine the dynamic changes
occurring in protein structure and protein turnover. We will use different types of samples and model systems
to capitalize on the advantages of each. In SPECIFIC AIM 1, we propose to target proteins involved in AD
in human cerebrospinal fluid with limited proteolysis to assess differences in protease accessibility
where there were minimal changes in protein levels. By measuring changes in protease accessibility, we
will gain insight into protein conformational changes. In SPECIFIC AIM 2, we will extend limited proteolysis
to mouse brain to investigate differences in protease accessibility due to aging. In SPECIFIC AIM 3, we
will examine protein turnover in 5 regions of mouse brain to reveal proteins with abnormal renewal
related to aging. Measuring protein turnover requires the use of stable isotope labeling, which precludes the
use of human samples. A benefit of using proteomic methods in this project is that we can examine many
features at once and return to the data with new hypotheses in the future. The feasibility of the project is
supported by the preliminary data generated for SPECIFIC AIM 1 and 2 and previous work done in the lab
using the method proposed for SPECIFIC AIM 3. This proposal will be the first use of limited proteolysis-mass
spectrometry with cerebrospinal fluid and brain tissue and the first example of protein turnover being studied in
more than 2 regions of brain tissue. The results from both Aims will improve our understanding of proteostasis
and deepen our understanding of the aging brain, Alzheimer’s disease, and other neurodegenerative diseases.
This project will occur in a collaborative, interdisciplinary research environment in the University of Washington
Genome Sciences department under the mentorship of Dr. Michael J. MacCoss, and the project will provide
training in aging, Alzheimer’s disease, neurodegenerative diseases, statistics, and quantitative proteomics.

## Key facts

- **NIH application ID:** 10294947
- **Project number:** 5F31AG066318-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** DANIELLE FAIVRE
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $40,805
- **Award type:** 5
- **Project period:** 2020-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10294947

## Citation

> US National Institutes of Health, RePORTER application 10294947, Monitoring alterations of proteostasis in aging and Alzheimer's disease (5F31AG066318-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10294947. Licensed CC0.

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