The Synaptic Vesicle Protein 2A Interacts With Key Pathogenic Factors in Alzheimer's Disease: Implications for Treatment.

Yanyan Kong,Weihao Li,Donglang Jiang,Yihui Guan,Ruiqing Ni,Cuiping Liu,Fang Xie,Xuanting Liu,Lin Huang,Yinping Zhou,Chencheng Zhang,Jiao Wang,Weiyan Zhou,Shibo Zhang,Bomin Sun,Zhengwei Zhang

doi:10.3389/fcell.2021.609908

Abstract

Alzheimer’s disease (AD), a serious neurodegenerative disease, is pathologically characterized by synaptic loss and dysfunction. Synaptic vesicle protein 2A (SV2A) is an indispensable vesicular protein specifically expressed in synapses and can be used as a biomarker for synaptic density. We found that the expression of SV2A was down-regulated in the hippocampus of AD patients, yet the relation of SV2A to other hallmarks of AD pathology such as amyloid precursor protein (APP), β-amyloid (Aβ), and Tau protein is not thoroughly clear. In addition, SV2A colocalized with APP and was down-regulated at Aβ deposition. Moreover, we found that SV2A deficiency leads to a simultaneous increase in Aβ and Tau hyperphosphorylation, while SV2A overexpression was associated with downregulation of β-site APP cleaving enzyme 1 and apolipoprotein E genes. In addition, evidence gained in the study points to the phosphatidylinositol 3-kinase signaling pathway as a possible mediator in SV2A regulation influencing the incidence and development of AD. With limited effective diagnostic methods for AD, a close interplay between SV2A and AD-related proteins demonstrated in our study may provide novel and innovative diagnostic and therapeutic opportunities.

Highlights

Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease associated with aging (Heneka et al, 2015; Turab Naqvi et al, 2020)
We found that Aβ expressions were significantly increased in certain brain regions of SV2A-overexpressing virus (SV2A)-knockout (KO) mice by positron emission tomography (PET) imaging techniques
We investigated the β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) and the apolipoprotein E genes (APOE), two other genes associated with AD, for their relationship with SV2A

Summary

Introduction

Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease associated with aging (Heneka et al, 2015; Turab Naqvi et al, 2020). The primary component of senile plaques is β-amyloid (Aβ), which is secreted as an enzymatic digestion product of amyloid β-protein precursor (APP) by hydrolase (Myllykangas et al, 2002; Reed-Geaghan et al, 2009; Magnoni et al, 2012; Kummer et al, 2015), while neurofibrillary tangles are composed of hyperphosphorylated tau proteins (Noble et al, 2013; Rodriguez-Martin et al, 2013; Pooler et al, 2014; Frost et al, 2015; Mcinnes et al, 2018; Turab Naqvi et al, 2020). Understanding the pathogenic mechanisms of Aβ and tau in the AD brain is important for AD prevention and treatment (Buckley and Kelly, 1985; Ma et al, 2018; Mcinnes et al, 2018)

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Conclusion