# Cell Type-Specific Proteins that Promote Resilience to Cognitive Aging and Alzheimer's Disease (Suppl)

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $56,123

## Abstract

PROJECT SUMMARY/ABSTRACT
Resilience to brain aging and Alzheimer’s Disease (AD) is a phenomenon whereby cognitive functioning is
better than predicted based on chronological age, genetic risk and/or advanced neuropathology, likely because
of the presence of as yet unidentified protective factors. These factors, once identified, are expected to provide
key targets for treatment and prevention of AD. However, significant barriers limit discovery of the genetic
mechanisms of resilience using human genetic methods alone, including: difficulties in identifying large
numbers of individuals with asymptomatic AD, extracting age and interacting genetic effects from complex
human genomes, controlling environmental factors, and obtaining brain tissue from asymptomatic AD cases.
Moreover, it is well known that transcript abundance is not sufficient to infer protein abundance, as they differ
spatially, temporally, and in response to learning tasks. Yet, our ability to discern how proteomes change
across aging and AD progression is limited by the impossibility of longitudinal molecular analyses on human
brain tissues, as well as the technology needed to profile cell type-specific proteomes associated with
susceptibility versus resilience to AD. To fill these significant technological and knowledge gaps, here we will
develop a robust pipeline using the most translationally relevant mouse models of human brain aging and AD
(i.e., the AD-BXDs and their non-transgenic Ntg-BXDs controls) to obtain a longitudinal knowledge base of
proteomes in specific cell types that we have found to exhibit robust changes in gene expression associated
with highly susceptible and highly resilient phenotypes. We will focus on the hippocampus as it is required for
spatial memory formation and recall in mice and humans, and hippocampus-dependent memory deficits are
common in AD. Indeed, our work and preliminary data suggest that mouse strain differences in the age at
onset and progression of cognitive deficits in the AD-BXDs (from extremely susceptible to resilient) result from
cell type-specific differences in gene expression in the hippocampus. We will integrate these mouse data with
clinical and omics data from NIA-sponsored AMP-AD and Resilience-AD Consortia to identify molecular drivers
of cognitive resilience. In Aim 1, we will identify cell type-specific changes in neuron and microglia protein
expression associated with resilience to AD using bioorthogonal non-canonical amino acid tagging (BONCAT)
in AD-BXDs. In Aim 2, we will translate drivers and molecular networks underlying cognitive resilience to
human AD cohorts. In Aim 3, we will leverage genetic engineering to functionally validate ‘in-hand’ resilience
candidates by determining their effects on memory, hippocampal neuronal excitability, and synaptic plasticity in
CRISPRed AD-BXDs. Using this pipeline, we will thereby discover novel and translationally relevant proteins
and complexes for consideration under AMPAD/TREAT-A...

## Key facts

- **NIH application ID:** 10942421
- **Project number:** 3R01AG075818-03S1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** CATHERINE COOK KACZOROWSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $56,123
- **Award type:** 3
- **Project period:** 2021-09-30 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10942421

## Citation

> US National Institutes of Health, RePORTER application 10942421, Cell Type-Specific Proteins that Promote Resilience to Cognitive Aging and Alzheimer's Disease (Suppl) (3R01AG075818-03S1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10942421. Licensed CC0.

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