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

Research output: Contribution to journalArticle

  • 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
Original languageEnglish
Article number10934
Number of pages12
JournalScientific Reports
DateAccepted/In press - 8 May 2015
DatePublished (current) - 9 Jun 2015


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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