Document Detail


Endocannabinoids prevent β-amyloid-mediated lysosomal destabilization in cultured neurons.
MedLine Citation:
PMID:  20923768     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Janis Noonan; Riffat Tanveer; Allan Klompas; Aoife Gowran; Joanne McKiernan; Veronica A Campbell
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-05
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-11-29     Completed Date:  2010-12-30     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  38543-54     Citation Subset:  IM    
Affiliation:
Department of Physiology, School of Medicine and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
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MeSH Terms
Descriptor/Qualifier:
Alzheimer Disease / drug therapy,  metabolism*,  pathology
Amyloid beta-Peptides / metabolism*
Animals
Apoptosis
Cannabinoid Receptor Modulators / metabolism*,  pharmacology
Cell Survival
Cells, Cultured
Endocannabinoids*
Intracellular Membranes / metabolism*,  pathology
Lysosomes / metabolism*,  pathology
Male
Neurons / metabolism*,  pathology
Permeability
Rats
Rats, Wistar
Receptors, Cannabinoid
Tumor Suppressor Protein p53 / metabolism
Up-Regulation
Chemical
Reg. No./Substance:
0/Amyloid beta-Peptides; 0/Cannabinoid Receptor Modulators; 0/Endocannabinoids; 0/Receptors, Cannabinoid; 0/Tumor Suppressor Protein p53
Comments/Corrections

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