# Spindle Assembly Checkpoint Silencing

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $384,735

## Abstract

ABSTRACT
Patients with Alzheimer’s disease (AD), a neurogenerative disorder resulting in dementia, accumulate beta-
amyloid (Aβ) plaques. Recently, it has been shown that this accumulation of Aβ results in the downregulation
of the ubiquitin ligase known as the Anaphase-Promoting Complex/Cyclosome (APC), leading to an
accumulation of its substrates, excitotoxicity, and apoptosis. However, a mechanistic understanding of how the
deregulation of the APC contributes to AD is unclear. We aim to dissect this process using a comprehensive
approach involving enzyme kinetics, cell-based assays, and mouse models in to understand which APC
substrates are elevated in AD (Aim 1) and how can we reactivate the APC in AD mouse models (Aim 2).
Based on preliminary data funded by the existing MIRA, we have uncovered a novel mechanism of APC
activation that could be harnessed to rescue the downregulation of APC activity observed in AD. Therefore,
this project specifically relates to the Notice of Special Interest: Alzheimer’s-focused administrative
supplements for NIH grants that are not focused on Alzheimer’s disease, for multiple reasons. First, Dr. Brown
is an early career investigator with expertise in the regulation of and by the APC. As the APC is paramount in
the signaling of the Spindle Assembly Checkpoint, which is the focus of funded MIRA, Dr. Brown is ideally
suited to apply his reagents and techniques to examine the role of the APC in AD. Second, he will firmly
establish a new collaboration with an accomplished investigator in the AD field Dr. Juan Song, who will mentor
Dr. Brown to address a significant basic science gap. Taken together, information generated from the
proposed research will stimulate additional activities, solidify a new collaboration for an R01 proposal in the
future, provide a foundation for a new structural biologist to enter the AD field, and may enable the
development of novel AD therapeutics.

## Key facts

- **NIH application ID:** 10123227
- **Project number:** 3R35GM128855-03S1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Nicholas Gene Brown
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $384,735
- **Award type:** 3
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123227

## Citation

> US National Institutes of Health, RePORTER application 10123227, Spindle Assembly Checkpoint Silencing (3R35GM128855-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10123227. Licensed CC0.

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