TY - JOUR T1 - Human brain-derived Aβ oligomers bind to synapses and disrupt synaptic activity in a manner that requires APP JF - bioRxiv DO - 10.1101/135673 SP - 135673 AU - Zemin Wang AU - Rosemary J. Jackson AU - Wei Hong AU - Taylor M. Walter AU - Arturo Moreno AU - Wen Liu AU - Shaomin Li AU - Matthew P. Frosch AU - Inna Slutsky AU - Tracy Young-Pearse AU - Tara L. Spires-Jones AU - Dominic M. Walsh Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/05/09/135673.abstract N2 - Compelling genetic evidence links the amyloid precursor protein (APP) to Alzheimer’s disease (AD), and several theories have been advanced to explain the involvement of APP in AD. A leading hypothesis proposes that a small amphipathic fragment of APP, the amyloid β-protein (Aβ), self-associates to form soluble aggregates which impair synaptic and network activity. Here, we report on the plasticity-disrupting effects of Aβ isolated from AD brain and the requirement of APP for these effects. We show that Aβ-containing AD brain extracts block hippocampal long-term potentiation (LTP), augment glutamate release probability and disrupt the excitation/inhibition balance. Notably, these effects are associated with Aβ localizing to synapses, and genetic ablation of APP prevents both Aβ binding and Aβ-mediated synaptic dysfunctions. These findings indicate a role for APP in AD pathogenesis beyond the generation of Aβ and suggest modulation of APP expression as a therapy for AD.Acknowledgments We thank Dr. Tiernan T. O’Malley for useful discussions and technical advice. This work was supported by grants to DMW from the National Institutes of Health (AG046275), Bright Focus, and the United States-Israel Binational Science Foundation (2013244, DMW and IS); grants to TSJ from Alzheimer’s Research UK and the Scottish Government (ARUK-SPG2013-1), Wellcome Trust-University of Edinburgh Institutional Strategic Support funds, and the H2020 European Research Council (ALZSYN); and to the Massachusetts Alzheimer’s Disease Research Center (AG05134). ER -