The endocannabinoid, anandamide, augments Notch-1 signaling in cultured cortical neurons exposed to amyloid-β and in the cortex of aged rats.
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 Aβ(1-42) 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 Aβ(1-42). AEA was found to induce a preferential processing of Notch-1 over amyloid precursor protein to generate Aβ(1-40). 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.
Department of Physiology, School of Medicine and Trinity College Institute of Neuroscience, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
Riffat
R
Tanveer
Aoife
A
Gowran
Janis
J
Noonan
Sinead E
SE
Keating
Andrew G
AG
Bowie
Veronica A
VA
Campbell
D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D063388:Endocannabinoids / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005989:Glycerides / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
D016229:Amyloid beta-Peptides; D001095:Arachidonic Acids; D001549:Benzamides; D002219:Carbamates; D063388:Endocannabinoids; D005989:Glycerides; D008562:Membrane Glycoproteins; C497763:Notch1 protein, rat; D010446:Peptide Fragments; D053284:Polyunsaturated Alkamides; D051881:Receptor, Notch1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C413604:nicastrin protein; C094503:glyceryl 2-arachidonate; D053829:Amyloid Precursor Protein Secretases; C078814:anandamide