| First Author | Wang Z | Year | 2017 |
| Journal | J Neurosci | Volume | 37 |
| Issue | 49 | Pages | 11947-11966 |
| PubMed ID | 29101243 | Mgi Jnum | J:336388 |
| Mgi Id | MGI:6103445 | Doi | 10.1523/JNEUROSCI.2009-17.2017 |
| Citation | Wang Z, et al. (2017) Human Brain-Derived Abeta Oligomers Bind to Synapses and Disrupt Synaptic Activity in a Manner That Requires APP. J Neurosci 37(49):11947-11966 |
| abstractText | 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 beta-protein (Abeta), self-associates to form soluble aggregates that impair synaptic and network activity. Here, we used the most disease-relevant form of Abeta, protein isolated from AD brain. Using this material, we show that the synaptotoxic effects of Abeta depend on expression of APP and that the Abeta-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 Abeta localizing to synapses and binding of soluble Abeta aggregates to synapses requires the expression of APP. Our findings indicate a role for APP in AD pathogenesis beyond the generation of Abeta and suggest modulation of APP expression as a therapy for AD.SIGNIFICANCE STATEMENT Here, we report on the plasticity-disrupting effects of amyloid beta-protein (Abeta) isolated from Alzheimer''s disease (AD) brain and the requirement of amyloid precursor protein (APP) for these effects. We show that Abeta-containing AD brain extracts block hippocampal LTP, augment glutamate release probability, and disrupt the excitatory/inhibitory balance. These effects are associated with Abeta localizing to synapses and genetic ablation of APP prevents both Abeta binding and Abeta-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. |
