# Polarity determinants in endolysosomal trafficking and proteostasis: Implications for Alzheimer's disease pathogenesis

> **NIH NIH R21** · RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL · 2020 · $198,750

## Abstract

Project Summary
 The vast majority of Alzheimer’s disease (AD) is sporadic, with aging being the biggest risk factor. Yet
age-related changes within neurons that can drive the AD pathogenic process remain elusive. Intriguingly,
there is an intricate link between the aging process and cell polarity. Dysregulation of polarity is observed in
many cellular contexts during aging, such as increased permeability of epithelial barriers, defective asymmetric
division of stem cells and increased frequency of cancer. However, whether brain aging and Alzheimer’s
disease result from polarity dysregulation is unknown. Research in our laboratory has focused on the
partitioning defective (Par) polarity proteins in neuronal development and degeneration. Interestingly, our
recent studies point to a key role for Par3 in the pathogenesis of AD. AD is characterized by plaques
composed of β-amyloid (Aβ), which is derived from amyloid precursor protein (APP) through cleavage by β-
and γ-secretases. The rate-limiting step of Aβ generation is the convergence between APP and its β-secretase
BACE1. We found Par3 expression is significantly reduced by middle-age, and loss of Par3 is common in
human AD brains. In addition, Par3 depletion causes a significant increase in APP and BACE1 convergence.
Unexpectedly, we found Aβ accumulates intracellularly in the absence of Par3. Further studies suggest this is
caused by defective autophagosome clearance. Remarkably, accumulation of autophagosomes and other
autophagic vacuoles is also characteristic of the AD brain. Thus, these exciting data have led to our
hypothesis that loss of Par3 in the aging brain promotes AD progression by targeting both APP/BACE1
convergence and autophagy. Dysregulation of these processes will lead to intracellular Aβ accumulation,
which is highly toxic to neurons. We will test our hypothesis through two aims. In Aim 1, we will elucidate the
mechanism by which Par3 regulates APP and BACE1 convergence and intracellular Aβ accumulation. In Aim
2, we will examine the mechanism by which Par3 regulates autophagy and lysosome functions. We will use a
combination of BiFC, optogenetic manipulation of Par protein activity, as well as in vivo analysis in forebrain-
specific Par3 conditional knockout mice. Together, our proposed studies will establish the molecular
mechanisms by which Par polarity proteins are involved in AD pathogenesis. The results will shed light on the
mechanism of sporadic AD in which aging is the major risk factor and polarity dysregulation may be the
common feature.

## Key facts

- **NIH application ID:** 9912086
- **Project number:** 5R21AG063123-02
- **Recipient organization:** RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
- **Principal Investigator:** Huaye Zhang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $198,750
- **Award type:** 5
- **Project period:** 2019-04-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9912086

## Citation

> US National Institutes of Health, RePORTER application 9912086, Polarity determinants in endolysosomal trafficking and proteostasis: Implications for Alzheimer's disease pathogenesis (5R21AG063123-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9912086. Licensed CC0.

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