%0 Journal Article
%T Human Brain-Derived A¦Â Oligomers Bind to Synapses and Disrupt Synaptic Activity in a Manner That Requires APP
%A Arturo Moreno
%A Dominic M. Walsh
%A Grant T. Corbett
%A Inna Slutsky
%A Matthew P. Frosch
%A Rosemary J. Jackson
%A Shaomin Li
%A Tara L. Spires-Jones
%A Tracy L. Young-Pearse
%A Walter M. Taylor
%A Wei Hong
%A Wen Liu
%A Zemin Wang
%J The Journal of Neurosience
%D 2017
%R 10.1523/JNEUROSCI.2009-17.2017
%X Compelling genetic evidence links the amyloid precursor protein (APP) to Alzheimer's disease (AD) and several theories have been advanced to explain the relationship. A leading hypothesis proposes that a small amphipathic fragment of APP, the amyloid ¦Â-protein (A¦Â), self-associates to form soluble aggregates that impair synaptic and network activity. Here, we used the most disease-relevant form of A¦Â, protein isolated from AD brain. Using this material, we show that the synaptotoxic effects of A¦Â depend on expression of APP and that the A¦Â-mediated impairment of synaptic plasticity is accompanied by presynaptic effects that disrupt the excitatory/inhibitory (E/I) balance. The net increase in the E/I ratio and inhibition of plasticity are associated with A¦Â localizing to synapses and binding of soluble A¦Â aggregates to synapses requires the expression of APP. Our findings indicate a role for APP in AD pathogenesis beyond the generation of A¦Â and suggest modulation of APP expression as a therapy for AD.

SIGNIFICANCE STATEMENT Here, we report on the plasticity-disrupting effects of amyloid ¦Â-protein (A¦Â) isolated from Alzheimer's disease (AD) brain and the requirement of amyloid precursor protein (APP) for these effects. We show that A¦Â-containing AD brain extracts block hippocampal LTP, augment glutamate release probability, and disrupt the excitatory/inhibitory balance. These effects are associated with A¦Â localizing to synapses and genetic ablation of APP prevents both A¦Â binding and A¦Â-mediated synaptic dysfunctions. Our results emphasize the importance of APP in AD and should stimulate new studies to elucidate APP-related targets suitable for pharmacological manipulation
%U http://www.jneurosci.org/content/37/49/11947