title: Loss of CB1 receptors leads to decreased cathepsin D levels and accelerated lipofuscin accumulation in the hippocampus.
abstract: Early onset of age-related changes in the brain of cannabinoid 1 receptor knockout (Cnr1(-/-)) mice suggests that cannabinoid 1 (CB1) receptor activity significantly influences the progression of brain aging. In the present study we show that lack of CB1 receptors leads to a significant increase in lipofuscin accumulation and a reduced expression and activity of cathepsin D, lysosomal protease implicated in the degradation of damaged macromolecules, in the hippocampus of 12-month-old mice. The impaired clearance of damaged macromolecules due to the low cathepsin D levels and not enhanced oxidative stress may be responsible for the lipofuscin accumulation because macromolecule oxidation levels were comparable between the genotypes within the same age group. The altered levels of autophagy markers p62 and LC3-II suggest that autophagy is upregulated in CB1 knockout mice. Increased autophagic flux in the absence of CB1 receptors is probably a compensatory mechanism to partially counteract decreased lysosomal degradation capacity. Together, these results suggest that CB1 receptor activity affects lysosomal activity, degradation of damaged macromolecules and thus it may influence the course and onset of brain aging.
authors: Institute of Molecular Psychiatry, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
authors: Anastasia
authors: A
authors: Piyanova
authors: Onder
authors: O
authors: Albayram
authors: Carlo Alberto
authors: CA
authors: Rossi
authors: Hany
authors: H
authors: Farwanah
authors: Kerstin
authors: K
authors: Michel
authors: Pierluigi
authors: P
authors: Nicotera
authors: Konrad
authors: K
authors: Sandhoff
authors: Andras
authors: A
authors: Bilkei-Gorzo
mesh_terms: D000375:Aging; D000818:Animals; D001343:Autophagy; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002402:Cathepsin D / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D007249:Inflammation; D015227:Lipid Peroxidation; D008062:Lipofuscin / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: C578453:CNR1 protein, mouse; D063388:Endocannabinoids; D008062:Lipofuscin; D043884:Receptor, Cannabinoid, CB1; D002402:Cathepsin D; C533923:Ctsd protein, mouse; D010100:Oxygen
keywords: Autophagy; Endocannabinoid system; Hippocampus; LC3; Oxidative stress; p62