期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 75, 期 1, 页码 173-185出版社
IOS PRESS
DOI: 10.3233/JAD-200071
关键词
Alzheimer's disease; amyloid-beta; BACE1; SV2B; synapse
资金
- JSPS [18K15365]
- ISHIZUE 2015 of Kyoto University Research Development Program
- Grants-in-Aid for Scientific Research [18K15365] Funding Source: KAKEN
Background: Given that amyloid-beta (A beta) peptide is produced and released at synapses, synaptic A beta is one of the promising therapeutic targets to prevent synaptic dysfunction in Alzheimer's disease (AD). Although A beta production begins with the cleavage of the amyloid-beta protein precursor (A beta PP) by beta-site A beta PP cleaving enzyme 1 (BACE1), the mechanism on how BACE1 is involved in A beta PP processing at synapses remains unclear. Objective: This study aimed to identify novel BACE1 interacting proteins regulating Ap production at the synapse. Methods: BACE1 interacting proteins were pulled down using a mass spectrometry-based proteomics of wild-type (WT) rat brain synaptoneurosome lysates utilizing anti-BACE1 antibody. Then, a novel BACE1 interactor was identified and characterized using experimental systems that utilized transfected cells and knockout (KO) mice. Results: Synaptic vesicle protein 2B (SV2B) was identified as a novel presynaptic interaction partner of BACE1. In HEK293 cells, co-overexpression of SV2B with BACE1 significantly reduced the sA beta PP beta and A beta levels released in the media; thus, SV2B overexpression negatively affected the A beta PP cleavage by BACE1. Compared with those of WT mice, the hippocampal lysates of SV2B knockout mice had significantly elevated A beta levels, whereas the beta-secretase activity and the A beta PP and BACE1 protein levels remained unchanged. Finally, a fractionation assay revealed that BACE1 was mislocalized in SV2B KO mice; hence, SV2B may be involved in BACE1 trafficking downregulating the amyloidogenic pathway of A beta PP. Conclusion: SV2B has a novel role of negatively regulating the amyloidogenic processing of A beta PP at the presynapses.
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