The endocannabinoid, anandamide, augments notch-1 signaling in cultured cortical neurons exposed to amyloid- β and in the cortex of aged rats

Riffat Tanveer, Aoife Gowran, Janis Noonan, Sinead E. Keating, Andrew G. Bowie, Veronica A. Campbell

Research output: Contribution to journalArticle

Abstract

Aberrant Notch signaling has recently emerged as a possible mechanism for the altered neurogenesis, cognitive impairment, and learning and memory deficits associated with Alzheimer disease (AD). Recently, targeting the endocannabinoid system in models of AD has emerged as a potential approach to slow the progression of the disease process. Although studies have identified neuroprotective roles for endocannabinoids, there is a paucity of information on modulation of the pro-survival Notch pathway by endocannabinoids. In this study the influence of the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol, on the Notch-1 pathway and on its endogenous regulators were investigated in an in vitro model of AD. We report that AEA up-regulates Notch-1 signaling in cultured neurons. We also provide evidence that although Aβ1-42 increases expression of the endogenous inhibitor of Notch-1, numb (Nb), this can be prevented by AEA and 2-arachidonoylglycerol. Interestingly, AEA up-regulated Nct expression, a component of γ-secretase, and this was found to play a crucial role in the enhanced Notch-1 signaling mediated by AEA. The stimulatory effects of AEA on Notch-1 signaling persisted in the presence of Aβ1-42. AEA was found to induce a preferential processing of Notch-1 over amyloid precursor protein to generate Aβ1-40. Aging, a natural process of neurodegeneration, was associated with a reduction in Notch-1 signaling in rat cortex and hippocampus, and this was restored with chronic treatment with URB 597. In summary, AEA has the proclivity to enhance Notch-1 signaling in an in vitro model of AD, which may have relevance for restoring neurogenesis and cognition in AD.

Original languageEnglish
Pages (from-to)34709-34721
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number41
DOIs
Publication statusPublished - Oct 5 2012

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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