Amyloid-β oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice

Kelly T. Dineley, Rakez Kayed, Volker Neugebauer, Yu Fu, Wenru Zhang, Lindsay C. Reese, Giulio Taglialatela

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

Soluble oligomeric aggregates of the amyloid-β (Aβ) peptide are believed to be the most neurotoxic Aβ species affecting the brain in Alzheimer disease (AD), a terminal neurodegenerative disorder involving severe cognitive decline underscored by initial synaptic dysfunction and later extensive neuronal death in the CNS. Recent evidence indicates that Aβ oligomers are recruited at the synapse, oppose expression of long-term potentiation (LTP), perturb intracellular calcium balance, disrupt dendritic spines, and induce memory deficits. However, the molecular mechanisms behind these outcomes are only partially understood; achieving such insight is necessary for the comprehension of Aβ-mediated neuronal dysfunction. We have investigated the role of the phosphatase calcineurin (CaN) in these pathological processes of AD. CaN is especially abundant in the CNS, where it is involved in synaptic activity, LTP, and memory function. Here, we describe how oligomeric Aβ treatment causes memory deficits and depresses LTP expression in a CaN-dependent fashion. Mice given a single intracerebroventricular injection of Aβ oligomers exhibited increased CaN activity and decreased pCREB, a transcription factor involved in proper synaptic function, accompanied by decreased memory in a fear conditioning task. These effects were reversed by treatment with the CaN inhibitor FK506. We further found that expression of hippocampal LTP in acutely cultured rodent brain slices was opposed by Aβ oligomers and that this effect was also reversed by FK506. Collectively, these results indicate that CaN activation may play a central role in mediating synaptic and memory disruption induced by acute oligomeric Aβ treatment in mice.

Original languageEnglish (US)
Pages (from-to)2923-2932
Number of pages10
JournalJournal of Neuroscience Research
Volume88
Issue number13
DOIs
StatePublished - Oct 1 2010

Keywords

  • Alzheimer disease
  • LTP
  • PP-2B
  • pCREB

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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