# Elucidating the contribution of amyloidogenic APP processing to AD-relevant impaired synaptic protein turnover

> **NIH NIH F31** · NORTHWESTERN UNIVERSITY · 2024 · $48,974

## Abstract

Project Summary
Alzheimer’s disease (AD) is a debilitating neurodegenerative disease and the most prevalent form
of dementia. AD is pathologically characterized by two misfolded and aggregated proteins:
amyloid-beta peptides (Aβ42) and hyperphosphorylated tau. Although Aβ42 accumulation,
produced amyloidogenic processing of the amyloid precursor protein (APP), is one of the earliest
pathological events, the initial trigger in proteostasis imbalance remains unknown. To investigate
proteostasis impairments in AD, our research utilizes metabolic pulse-chase (pc) labeling with
stable isotopes in combination with quantitative mass spectrometry (MS) based proteomic
analysis. Using this strategy with the recently developed APP knock-in (App KI) mouse models of
amyloid pathology, we discovered that axon terminals are selective sites of impaired protein
degradation, specifically synaptic vesicle (SV) and SV-associated proteins. This alteration
occurred before plaque pathology or elevated Aβ42 levels. This is important as it suggests we
have identified the earliest synaptic impairment in protein turnover that occurs before amyloid
pathology. Additionally, I recently discovered that targeting SVs with small molecule antiepileptic
drug levetiracetam in App KI mice mitigated AD pathology by decreasing Aβ42 accumulation via
alteration of amyloidogenic processing of APP. The goal of my proposed project is to uncover the
mechanism for impaired synaptic proteostasis in models of preclinical amyloid pathology that may
underlie the initial trigger in the cascade of pathologies seen in AD. One mechanism for turnover
at the presynapse is thought to rely on the ubiquitin-proteasome system (UPS) marking proteins
for transport out of the axon terminal to the soma for degradation. The central hypothesis of my
proposal is that amyloidogenic processing of APP leads to a deficit to this key process resulting
in an impairment in axon terminal protein turnover. To address if disrupting this process impairs
axon terminal proteostasis, I propose the following aims. First, I will investigate in vivo if the UPS
is disrupted in App KI brains using previously pc-ed tissue and advanced MS techniques for
isolation and quantification of ubiquitinated proteins. Second, I will determine if disruptions in SV
transport result from amyloidogenic processing of APP and if this leads to mislocalization of APP
in vitro and finally will confirm these findings in human neurons derived from AD patients. Taken
all together, this proposed project will determine the initial mechanisms of AD-relevant protein
degradation impairments, crucial to determining the cause of protein accumulation in AD which
currently remains unknown.

## Key facts

- **NIH application ID:** 10745290
- **Project number:** 5F31AG079653-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Nalini Rao
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745290

## Citation

> US National Institutes of Health, RePORTER application 10745290, Elucidating the contribution of amyloidogenic APP processing to AD-relevant impaired synaptic protein turnover (5F31AG079653-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10745290. Licensed CC0.

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