# Dysregulated Ribosomal Protein Synthesis in Amyloid and Tau Mouse Models

> **NIH NIH R21** · NEW YORK UNIVERSITY · 2021 · $435,875

## Abstract

Abstract
It is known that protein homeostasis is impaired in Alzheimer’s disease (AD) and frontotemporal dementia (FTD).
A multitude of studies have indicated that the proteome is altered throughout the disease process, and ribosomal
dysfunction occurs prior to advanced disease states. We have previously shown that de novo protein synthesis
is impaired in APP/PS1 mutant mice, which express known human mutations associated with early-onset AD.
Mounting evidence suggests changes in cell functioning occur decades prior to the development of symptoms
in AD. In addition, the lack of success of clinical drug trials based on the amyloid hypothesis indicates greater
understanding of the AD process is necessary to develop novel and effective therapies. To address these issues,
we have used novel proteomic technology to label newly synthesized proteins in asymptomatic APP/PS1 mice,
as well as symptomatic APP/PS1 mice that exhibit AD-like memory deficits. Our preliminary studies indicate that
protein synthesis is dysregulated in these mice, and significant changes in the synthesis of protein components
of the ribosome are observed even prior to symptom onset. As these findings may underlie the pathology of this
proteopathy, we propose to investigate the impact of this ribosomal dysregulation and test our overall
hypothesis that that age-dependent alterations observed in the synthesis of specific ribosomal proteins
(RPs) in amyloid and tau model mice alter the translation of selective mRNAs that ultimately result in
synaptic and memory impairments. Moreover, as RP synthesis has recently been shown to be dysregulated in
the rTg4510 mouse model of AD- and FTD-like tauopathy, we hypothesize that alterations in RP synthesis in
response to AD- and FTD-like tau dysregulation could impact ribosomal protein content, and similarly affect
translational activity. We first will determine the RP content of functional ribosomes from asymptomatic and
symptomatic APP/PS1 mice. Then, we will determine the translational activity of ribosomes from AD model mice.
Finally, we will determine RP stoichiometry and translational activity of ribosomes from the K3 and PS19 mouse
models of tauopathy and neurodegeneration. The results of these experiments will further our understanding of
the neurodegenerative disease process, paving the way for similar investigations in AD and FTD patient cells,
and subsequently identifying therapeutic targets for the treatment of AD and FTD.

## Key facts

- **NIH application ID:** 10201329
- **Project number:** 1R21NS121786-01
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** Eric Klann
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $435,875
- **Award type:** 1
- **Project period:** 2021-04-15 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201329

## Citation

> US National Institutes of Health, RePORTER application 10201329, Dysregulated Ribosomal Protein Synthesis in Amyloid and Tau Mouse Models (1R21NS121786-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10201329. Licensed CC0.

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