# Molecular consequences of protein regulation on amyloid plaque burden

> **NIH NIH R03** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $155,500

## Abstract

PROJECT SUMMARY/ABSTRACT
 There are almost 6 million individuals with Alzheimer's disease (AD) in the United States, and current
predictions suggest over 14 million will be affected by 2050. AD is characterized pathologically by extracellular
amyloid plaques and neurofibrillary tangles. However, despite intense research focus on these features we still
don't understand the mechanistic basis for cognitive decline or how the plaques and tangles are involved. Age
is the largest risk factor for neurodegeneration but the molecular details that connect normal aging and
neurodegenerative diseases are unclear. Caloric restriction (CR) without malnutrition delays aging and age-
related diseases, including neurodegenerative diseases. A long-running trial of CR in the non-human primate
rhesus monkey at the University of Wisconsin-Madison (UW) has confirmed that the benefits of CR translate to
primates. Large-scale molecular profiling work to understand the CR response in these animals has revealed
general downregulation of growth, immune, and inflammatory pathways and upregulation of metabolic pathways.
The hepatic response to short-term CR included a novel role for RNA processing mechanisms such as alternative
splicing; changes to exon usage patterns were widespread across the metabolic network recruited by CR.
 Rhesus monkeys develop plaques spontaneously beginning around their median lifespan of 26 years of
age. Banked brain specimens from the UW Aging and CR study therefore represent a significant opportunity to
study AD pathology in the context of aging in a highly translatable model. The goal of this study is to use deep
sequencing proteomics to investigate the production of protein isoforms from RNA processing events and
determine how they correlate with amyloid plaque burden in three brain regions. These data will then be
integrated with RNAseq and other data already existing or in the process of being collected from these animals,
including tau, peripheral insulin sensitivity, microglia, cognition, metabolism, and other indices, ultimately
connecting RNA processing to downstream AD pathology and systemic metabolic health.

## Key facts

- **NIH application ID:** 10461965
- **Project number:** 5R03AG070686-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Timothy W. Rhoads
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $155,500
- **Award type:** 5
- **Project period:** 2021-08-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461965

## Citation

> US National Institutes of Health, RePORTER application 10461965, Molecular consequences of protein regulation on amyloid plaque burden (5R03AG070686-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10461965. Licensed CC0.

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