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

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.

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The Synaptic Vesicle Protein 2a Interacts With Key Pathogenic Factors in Alzheimer’s Disease: Implications for Treatment

10.21203/rs.3.rs-32584/v1 ◽

2020 ◽

Author(s):

Yanyan Kong ◽

Lin Huang ◽

Xuanting Liu ◽

Yinping Zhou ◽

Cuipin Liu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurological Diseases ◽

Future Research ◽

Simultaneous Increase ◽

Mrna Levels ◽

Pathogenic Factors ◽

Pi3k Signaling Pathway ◽

Vesicle Protein ◽

Related Proteins

Abstract Background:Alzheimer’s Disease(AD), a serious neurodegenerative disease,is pathologicallycharacterized 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. Nevertheless, the involvement of SV2A in the pathogenesis and development of ADand its relation to other hallmarks of AD pathology, such as amyloid precursor protein (APP), β-amyloid (Aβ), and tau protein are not fully understood.Methods:We first examined and compared the mRNA levels of SV2A in the hippocampus of AD patients and non-AD subject in the Allen Brain database,thenwe constructed SV2A knockout mouse model.Using PET imagingwe compared the expression of Aβ in SV2A knockout mice and WT mice, analyze the relationship between SV2A and AD related proteins by quantitative real-time polymerase chain reaction (PCR), western blotting and ELISA.Results:Our results showed thatthe expression of SV2A was downregulated in the hippocampus of AD patients.In addition,SV2A colocalized with APPandwas downregulated at Aβ deposition. Moreover, we used APPswe293T cells lines to either silence or overexpress SV2A and found that SV2A deficiency leads to a simultaneous increase in Aβand Tau hyperphosphorylation,whileSV2A overexpression was associated with down-regulation of BACE1 and APOE. In addition, evidence gained in the study points PI3K signaling pathway as a possible mediator in SV2A regulation influencing the incidence and development of AD. Conclusions:Our research demonstrated that SV2A is an important regulator of AD, close interplay between SV2A and AD related proteins demonstrated in our studyprovide novel diagnostic and therapeutic opportunities of AD. This study provides guidelines and information regarding the mechanism of SV2A influence in the regulation of AD and possible future research of neurological diseases.

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