Amyloid-β Oligomers May Impair SNARE-Mediated Exocytosis by Direct Binding to Syntaxin 1a.
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.
Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea.
Yoosoo
Y
Yang
Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea; Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, IA 50011, USA.
Jaewook
J
Kim
Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea.
Hye Yun
HY
Kim
Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea.
Nayeon
N
Ryoo
Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea.
Sejin
S
Lee
Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea.
YoungSoo
Y
Kim
Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea; Department of Neuroscience, University of Science and Technology (UST), Daejon 305-333, Republic of Korea. Electronic address: hrhim@kist.re.kr.
Hyewhon
H
Rhim
Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, Republic of Korea; Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, IA 50011, USA. Electronic address: colishin@iastate.edu.
Yeon-Kyun
YK
Shin
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D005089:Exocytosis; D051379:Mice; D011485:Protein Binding; D055503:Protein Multimerization; D050827:Syntaxin 1 / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D050827:Syntaxin 1