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

Yoosoo Yang, Jaewook Kim, Hye Yun Kim, Nayeon Ryoo, Sejin Lee, Young Soo Kim, Hyewhon Rhim, Yeon Kyun Shin

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)


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

Original languageEnglish
Article number1940
Pages (from-to)1244-1251
Number of pages8
JournalCell Reports
Issue number8
Publication statusPublished - 2015 Aug 25

Bibliographical note

Funding Information:
This work was supported by NIH grants (R01 GM051290; to Y.-K.S.), KIST Institutional Programs (2E25520 and 2E25023), KHIDI (HI14C3319), RF and the WISET Grant funded by the Ministry of Science (Republic of Korea), and MSIP under the Program for Returners into R&D (KW-2014-PPD-0076).

Publisher Copyright:
© 2015 The Authors.

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)


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