# Mechanism and modulation of Amyloid Precursor Protein proteolysis

> **NIH NIH R35** · UNIVERSITY OF MINNESOTA · 2020 · $382,262

## Abstract

A critical pathological hallmark of Alzheimer’s disease (AD) is plaque deposits in the brain
composed of aggregates of the small hydrophobic β-amyloid (Aβ) peptide. It is well known that
the 38-42 amino acid Aβ peptides at the crux of the prevalent “Amyloid Hypothesis” of AD
pathogenesis are generated by sequential proteolytic cleavages of the transmembrane
β-Amyloid precursor protein (APP). Two distinct proteolytic cascades lead to amyloidogenic
versus non-amyloidogenic fates . Moreover, multiple pathogenic AD mutations alter the flux
through these proteolytic pathways by unknown mechanisms. The lack of suitable assays to
control or detect proteolysis of APP has both hindered the understanding of how proteolysis is
regulated and the development of receptor specific modulators. We have recently developed a
synthetic Notch proteolysis assay (SNAPS) that harnesses the easy to control inputs and
outputs of Notch signaling to study proteolysis of diverse cell surface receptors by constructing
receptor-of-interest/Notch chimeras. We will use this assay to study mechanism and find
modulators of APP proteolysis. Aim 1: Determine how cellular environment, molecular
environment and Alzheimer’s disease mutations affect APP proteolysis. Aim 2: Discover APP
proteolytic modulators. We will identify nanobodies and single chain antibodies that bind to APP
and potentially modulate its proteolysis into Aβ .

## Key facts

- **NIH application ID:** 10123650
- **Project number:** 3R35GM119483-05S1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** WENDY RYAN GORDON
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,262
- **Award type:** 3
- **Project period:** 2016-07-20 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123650

## Citation

> US National Institutes of Health, RePORTER application 10123650, Mechanism and modulation of Amyloid Precursor Protein proteolysis (3R35GM119483-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10123650. Licensed CC0.

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