Human brain-derived Aβ oligomers bind to synapses and disrupt synaptic activity in a manner that requires APP

Zemin Wang, Rosemary J. Jackson, Wei Hong, Walter M. Taylor, Grant T. Corbett, Arturo Moreno, Wen Liu, Shaomin Li, Matthew P. Frosch, Inna Slutsky, Tracy L. Young-Pearse, Tara L. Spires-Jones, Dominic M. Walsh

Research output: Contribution to journalArticlepeer-review

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 Aβ, protein 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/I) 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.

Original languageEnglish
Pages (from-to)11947-11966
Number of pages20
JournalJournal of Neuroscience
Volume37
Issue number49
DOIs
StatePublished - 6 Dec 2017

Keywords

  • Alzheimer’s disease
  • Amyloid beta
  • Amyloid precursor protein
  • Array tomography
  • Long-term potentiation
  • Whole-cell patch-clamp

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