# APP mimetic peptide as a potential therapeutic target to reduce amyloid generation

> **NIH NIH R21** · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · 2021 · $453,750

## Abstract

Amyloid-β (Aβ) generation is a key pathological event in Alzheimer's disease (AD). Aβ is produced by the
sequential proteolytic processing of the amyloid precursor protein (APP) by β- and γ- secretases. APP
endocytosis is an important step in Aβ generation. APP is internalized to endosomes where APP is
cleaved by β-secretase, initiating the amyloidogenic pathway. The sorting signal that regulates APP
endocytic processing required for Aβ generation is the highly conserved endocytic YENPTY sequence
located in the cytoplasmic region of APP. APP mice that lack the endocytic YENPTY motif have reduced
APP internalization and lower brain Aβ levels. Through our studies, we found Mints (also known as APP
binding family A, APBA) are a family of neuronal adaptor proteins that bind directly to the endocytic
YENPTY motif of APP and are essential for regulating APP endocytosis and amyloidgenic processing. In
addition, Mints interact with presenilin-1 (PS1), the catalytic core of the γ-secretase complex, facilitating
APP-PS1 colocalization and promoting Aβ production. Further, we found that loss of any one of the three
Mint proteins decreases Aβ production in aging mice and mouse models of AD. Together, we hypothesize
that the APP-Mint interaction is a potential and novel therapeutic target to selectively reduce Aβ
production in AD. We identified a novel cell-permeable APP mimetic peptide (TAT-APPMP) that interferes
with the APP-Mint interaction. The TAT-APPMP is designed to outcompete endogenous APP binding to
Mints to reduce Aβ production. Preliminary data reveals that treatment of primary neuronal cultures from
an AD mouse model with TAT-APPMP reduced Aβ production with minimal toxicity. This provides
compelling evidence that the APP-Mint interface is a viable therapeutic target for AD treatment and is
expected to have strong translational implications. However, the biological characterization of the APPMP,
examining its specificity, efficacy and its potential for in vivo AD treatment is lacking. The overall goal of
this proposal is to determine the specificity of the cell-permeable APPMP to disrupt the APP-Mint
interaction and reduce Aβ accumulation in AD mouse models.

## Key facts

- **NIH application ID:** 10205688
- **Project number:** 1R21AG072433-01
- **Recipient organization:** BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
- **Principal Investigator:** ANGELA HO
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $453,750
- **Award type:** 1
- **Project period:** 2021-05-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10205688

## Citation

> US National Institutes of Health, RePORTER application 10205688, APP mimetic peptide as a potential therapeutic target to reduce amyloid generation (1R21AG072433-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10205688. Licensed CC0.

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