期刊
CELL REPORTS
卷 12, 期 8, 页码 1244-1251出版社
CELL PRESS
DOI: 10.1016/j.celrep.2015.07.044
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类别
资金
- NIH [R01 GM051290]
- KIST Institutional Programs [2E25520, 2E25023]
- KHIDI [HI14C3319]
- Ministry of Science (Republic of Korea)
- MSIP [KW-2014-PPD-0076]
Alzheimer's disease (AD) is closely associated with synaptic dysfunction, and thus current treatments often aim to stimulate neurotransmission to improve cognitive impairment. Whereas the formation of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is essential for synaptic transmission, the correlation between SNAREs and AD neuropathology is unknown. Here, we report that intracellular amyloid-beta (A beta) oligomers directly inhibit SNARE-mediated exocytosis by impairing SNARE complex formation. We observe abnormal reduction of SNARE complex levels in the brains of APP/PS1 transgenic (TG) mice compared to age-matched wild-types. We demonstrate that A beta oligomers block SNARE complex assembly through the direct interaction with a target membrane (t)-SNARE syntaxin 1a in vitro. Furthermore, the results of the in vitro single-vesicle content-mixing assay reveal that A beta oligomers inhibit SNARE-mediated fusion pores. Thus, our study identifies a potential molecular mechanism by which intracellular A beta oligomers hamper SNARE-mediated exocytosis, likely leading to AD-associated synaptic dysfunctions.
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