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

TY - JOUR

T1 - Human brain-derived Aβ oligomers bind to synapses and disrupt synaptic activity in a manner that requires APP

AU - Wang, Zemin

AU - Jackson, Rosemary J.

AU - Hong, Wei

AU - Taylor, Walter M.

AU - Corbett, Grant T.

AU - Moreno, Arturo

AU - Liu, Wen

AU - Li, Shaomin

AU - Frosch, Matthew P.

AU - Slutsky, Inna

AU - Young-Pearse, Tracy L.

AU - Spires-Jones, Tara L.

AU - Walsh, Dominic M.

N1 - Publisher Copyright: © 2017 the authors.

PY - 2017/12/6

Y1 - 2017/12/6

N2 - 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.

AB - 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.

KW - Alzheimer’s disease

KW - Amyloid beta

KW - Amyloid precursor protein

KW - Array tomography

KW - Long-term potentiation

KW - Whole-cell patch-clamp

UR - https://www.scopus.com/pages/publications/85037669452

U2 - 10.1523/JNEUROSCI.2009-17.2017

DO - 10.1523/JNEUROSCI.2009-17.2017

M3 - Article

C2 - 29101243

AN - SCOPUS:85037669452

SN - 0270-6474

VL - 37

SP - 11947

EP - 11966

JO - Journal of Neuroscience

JF - Journal of Neuroscience

IS - 49

ER -