1. Human Brain-Derived Aβ Oligomers Bind to Synapses and Disrupt Synaptic Activity in a Manner That Requires APP.
- Author
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Zemin Wang, Jackson, Rosemary J., Wei Hong, Taylor, Walter M., Corbett, Grant T., Moreno, Arturo, Wen Liu, Shaomin Li, Frosch, Matthew P., Slutsky, Inna, Young-Pearse, Tracy L., Spires-Jones, Tara L., and Walsh, Dominic M.
- Subjects
AMYLOID beta-protein precursor ,NEURODEGENERATION ,DRUG synergism ,ALZHEIMER'S disease treatment ,TAU proteins - Abstract
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 β-protein (Aβ), self-associates to form soluble aggregates that impair synaptic and network activity. Here, we used the most disease-relevant form of A β, protei n isolated from AD brain. Using this material, we show that the synaptotoxic effects of Aβ depend on expression of APP and that the Aβ-mediated impairment of synaptic plasticity is accompanied by presynaptic effects that disrupt the excitatory/inhibitory (E/l) balance. The net increase in the E/I ratio and inhibition of plasticity are associated with Aβ localizing to synapses and binding of soluble Aβ aggregates to synapses requires the expression of APP. Our 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. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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