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

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; Kei Cho

doi:10.1038/srep10934

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

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, Kei Cho^*

^*Corresponding author for this work

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Abstract

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.

Original language	English
Article number	10934
Number of pages	12
Journal	Scientific Reports
Volume	5
DOIs	https://doi.org/10.1038/srep10934
Publication status	Published - 9 Jun 2015

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Whitcomb, D. J., Hogg, E. L., Regan, P., Piers, T., Narayan, P., Whitehead, G., Winters, B. L., Kim, D. H., Kim, E., St George-Hyslop, P., Klenerman, D., Collingridge, G. L., Jo, J., & Cho, K. (2015). Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus. Scientific Reports, 5, Article 10934. https://doi.org/10.1038/srep10934

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title = "Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus",

abstract = "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.",

author = "Whitcomb, {Daniel J.} and Hogg, {Ellen L.} and Philip Regan and Thomas Piers and Priyanka Narayan and Garry Whitehead and Winters, {Bryony L.} and Kim, {Dong Hyun} and Eunjoon Kim and {St George-Hyslop}, Peter and David Klenerman and Collingridge, {Graham L.} and Jihoon Jo and Kei Cho",

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day = "9",

doi = "10.1038/srep10934",

language = "English",

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journal = "Scientific Reports",

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AU - Whitcomb, Daniel J.

AU - Hogg, Ellen L.

AU - Regan, Philip

AU - Piers, Thomas

AU - Narayan, Priyanka

AU - Whitehead, Garry

AU - Winters, Bryony L.

AU - Kim, Dong Hyun

AU - Kim, Eunjoon

AU - St George-Hyslop, Peter

AU - Klenerman, David

AU - Collingridge, Graham L.

AU - Jo, Jihoon

AU - Cho, Kei

PY - 2015/6/9

Y1 - 2015/6/9

N2 - 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.

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

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Acute stress causes rapid synaptic insertion of Ca2+ -permeable AMPA receptors to facilitate long-term potentiation in the hippocampus

Molecular mechanisms of long-term Depression int the hippocampus

THE EFFECTS OF ACUTE STRESS ON GLUTAMATE RECEPTOR TRAFFICKING AND SYNAPTIC PLASTICITY IN THE HIPPOCAMPUS

Dr Daniel Whitcomb

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

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Acute stress causes rapid synaptic insertion of Ca2+ -permeable AMPA receptors to facilitate long-term potentiation in the hippocampus

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Molecular mechanisms of long-term Depression int the hippocampus

THE EFFECTS OF ACUTE STRESS ON GLUTAMATE RECEPTOR TRAFFICKING AND SYNAPTIC PLASTICITY IN THE HIPPOCAMPUS

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Dr Daniel Whitcomb

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