Amyloid-? Oligomers May Impair SNARE-Mediated Exocytosis by Direct Binding to Syntaxin 1a.

ABSTRACT: 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-? (A?) 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? 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? oligomers inhibit SNARE-mediated fusion pores. Thus, our study identifies a potential molecular mechanism by which intracellular A? oligomers hamper SNARE-mediated exocytosis, likely leading to AD-associated synaptic dysfunctions.

SUBMITTER: Yang Y 

PROVIDER: S-EPMC4955600 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature