# Synaptic Vesicle Glycoprotein 2A Suppresses Amyloidogenesis Beyond Its Synaptic Role: A Novel Mechanism Disrupting BACE1 Binding and Altering APP Localization

## TL;DR

This study shows that SV2A, a brain protein, reduces amyloid plaques in Alzheimer's by blocking a key enzyme and changing where a harmful protein is located.

## Contribution

SV2A is newly identified as an APP-binding protein that suppresses amyloidogenesis by inhibiting BACE1-APP interaction.

## Key findings

- SV2A overexpression reduces Aβ plaque deposition in APP/PS1 mice.
- SV2A inhibits BACE1-APP interaction, suppressing amyloidogenic processing.
- SV2A alters APP localization away from endosomal-lysosomal compartments.

## Abstract

Synaptic vesicle glycoprotein 2A (SV2A), a transmembrane protein widely localized to synaptic vesicles, serves as a key indicator of synaptic loss in Alzheimer's disease (AD). In this study, adeno‐associated virus (AAV) was injected by brain stereotactic injection technique to construct SV2A‐overexpressing APP/PS1 mice, then the effects of SV2A on amyloid precursor protein (APP) degradation and its molecular mechanism were further explored in vivo or in vitro. Our results demonstrated that SV2A overexpression significantly reduced Aβ plaque deposition in brain tissue of APP/PS1 mice. Mechanistically, SV2A was identified as a novel APP‐binding protein that attenuated the amyloidogenic processing of APP by inhibiting its interaction with β‐site APP cleaving enzyme 1 (BACE1). Furthermore, SV2A overexpression altered the subcellular distribution of APP, shifting its localization away from the endosomal‐lysosomal compartments. Collectively, our findings unveil SV2A as a critical regulator of APP metabolism and propose it as a promising therapeutic target for intervening in the early pathological progression of AD.

Synaptic vesicle glycoprotein 2A, the newly identified APP‐binding protein, reduces amyloid‐β plaque deposition in Alzheimer's disease by suppressing the amyloidogenic pathway through inhibition of BACE1‐APP interaction and alteration of APP endosomal‐lysosomal localization.