Whitcomb, Daniel J.

Hogg, Ellen L.

Regan, Philip

Piers, Thomas

Narayan, Priyanka

Whitehead, Garry

Winters, Bryony L.

Kim, Dong Hyun

Kim, Eunjoon

St George-Hyslop, Peter

Klenerman, David

Collingridge, Graham L.

Jo, Jihoon

Cho, Kei

Scientific Reports

Daniel J. Whitcomb

Ellen L. Hogg

Philip Regan

Thomas Piers

Priyanka Narayan

Garry Whitehead

Bryony L. Winters

Dong-Hyun Kim

Eunjoon Kim

Peter St George-Hyslop

David Klenerman

Graham L. Collingridge

Jihoon Jo

Kwangwook Cho

MUCC (Crossref)

Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus

The acute neurotoxicity of oligomeric forms of amyloid-beta 1-42 (Abeta) is implicated in the pathogenesis of Alzheimer's disease (AD). However, how these oligomers might first impair neuronal function at the onset of pathology is poorly understood. Here we have examined the underlying toxic effects caused by an increase in levels of intracellular Abeta, an event that could be important during the early stages of the disease. We show that oligomerised Abeta induces a rapid enhancement of AMPA receptor-mediated synaptic transmission (EPSCA) when applied intracellularly. This effect is dependent on postsynaptic Ca(2+) and PKA. Knockdown of GluA1, but not GluA2, prevents the effect, as does expression of a S845-phosphomutant of GluA1. Significantly, an inhibitor of Ca(2+)-permeable AMPARs (CP-AMPARs), IEM 1460, reverses the increase in the amplitude of EPSCA. These results suggest that a primary neuronal response to intracellular Abeta oligomers is the rapid synaptic insertion of CP-AMPARs

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Anonymous

Biblioteca Digital de la Comunidad de Madrid

Boletín oficial de la provincia de Madrid: 19/12/1854

AbstractThe acute neurotoxicity of oligomeric forms of amyloid-β 1-42 (Aβ) is implicated in the pathogenesis of Alzheimer’s disease (AD). However, how these oligomers might first impair neuronal function at the onset of pathology is poorly understood. Here we have examined the underlying toxic effects caused by an increase in levels of intracellular Aβ, an event that could be important during the early stages of the disease. We show that oligomerised Aβ induces a rapid enhancement of AMPA receptor-mediated synaptic transmission (EPSCA) when applied intracellularly. This effect is dependent on postsynaptic Ca2+ and PKA. Knockdown of GluA1, but not GluA2, prevents the effect, as does expression of a S845-phosphomutant of GluA1. Significantly, an inhibitor of Ca2+-permeable AMPARs (CP-AMPARs), IEM 1460, reverses the increase in the amplitude of EPSCA. These results suggest that a primary neuronal response to intracellular Aβ oligomers is the rapid synaptic insertion of CP-AMPARs.</jats:p

Crossref

http://www.nature.com/articles/srep10934.pdf

Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus

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