Endocannabinoids prevent β-amyloid-mediated lysosomal destabilization in cultured neurons

Janis Noonan, Riffat Tanveer, Allan Klompas, Aoife Gowran, Joanne McKiernan, Veronica A. Campbell

Research output: Contribution to journalArticle

Abstract

Neuronal cell loss underlies the pathological decline in cognition and memory associated with Alzheimer disease (AD). Recently, targeting the endocannabinoid system in AD has emerged as a promising new approach to treatment. Studies have identified neuroprotective roles for endocannabinoids against key pathological events in the AD brain, including cell death by apoptosis. Elucidation of the apoptotic pathway evoked by β-amyloid (Aβ) is thus important for the development of therapeutic strategies that can thwart Aβ toxicity and preserve cell viability. We have previously reported that lysosomal membrane permeabilization plays a distinct role in the apoptotic pathway initiated by Aβ. In the present study, we provide evidence that the endocannabinoid system can stabilize lysosomes against Aβ-induced permeabilization and in turn sustain cell survival. We report that endocannabinoids stabilize lysosomes by preventing the Aβ-induced up-regulation of the tumor suppressor protein, p53, and its interaction with the lysosomal membrane. We also provide evidence that intracellular cannabinoid type 1 receptors play a role in stabilizing lysosomes against Aβ toxicity and thus highlight the functionality of these receptors. Given the deleterious effect of lysosomal membrane permeabilization on cell viability, stabilization of lysosomes with endocannabinoids may represent a novel mechanism by which these lipid modulators confer neuroprotection.

Original languageEnglish
Pages (from-to)38543-38554
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number49
DOIs
Publication statusPublished - Dec 3 2010

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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