title: Neuronal endosomal/lysosomal membrane destabilization activates caspases and induces abnormal accumulation of the lipid secondary messenger ceramide.
abstract: Impairment of endosomal/lysosomal functions are reported as some of the earliest changes in several age-related neurological disorders such as Alzheimer's disease. Dysregulation of the lysosomal system is also accompanied by the accumulation of age-associated pigments and several recent reports have indicated that this age-related lipofuscin accumulation can sensitize cells to oxidative stress and apoptotic cell death. In this study, we have established and evaluated an in vitro age-related pathology paradigm that models lipofuscin accumulation. Our model consists of the treatment of cultured primary mouse neurons with lysosomotropic detergents. We have observed that one of the earliest biochemical changes associated with lysosomotropic detergent-induced membrane instability is a loss of the endosomal/lysosomal proton gradient integrity, followed by an activation of sphingomyelin hydrolysis and ceramide accumulation within enlarged endosomal/lysosomal vesicles. In addition, we demonstrate that ceramide accumulation correlates with the activation of proximal procaspases-8 and -9 as well as distal caspase-3, prior to the appearance of cell death. Taken together, we propose that disturbances of the endosomal/lysosomal system, in addition to the activation of the sphingomyelinase hydrolysis cycle, play essential roles in the course of post-mitotic neuronal aging. The abnormal accumulation of undigested lipids and proteins within dysfunctional endosomal/lysosomal vesicle populations during the process of pathological aging may serve as triggers of the cell death programs that are associated with downstream neurodegeneration.
authors.affiliation: Dementia Research Program, Nathan Kline Institute, Orangeburg, NY, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Ditaranto-Desimone
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Saito
authors.forename: T L
authors.initials: TL
authors.lastname: Tekirian
authors.forename: Mariko
authors.initials: M
authors.lastname: Saito
authors.forename: Martin
authors.initials: M
authors.lastname: Berg
authors.forename: Gene
authors.initials: G
authors.lastname: Dubowchik
authors.forename: Brian
authors.initials: B
authors.lastname: Soreghan
authors.forename: Stefani
authors.initials: S
authors.lastname: Thomas
authors.forename: Neville
authors.initials: N
authors.lastname: Marks
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Yang
mesh_terms: D000818:Animals; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism*; D003902:Detergents / Q000494:pharmacology; D011992:Endosomes / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011247:Pregnancy; D015290:Second Messenger Systems / Q000502:physiology
chemical_list: D061945:Caspase Inhibitors; D002518:Ceramides; D003902:Detergents; D004791:Enzyme Inhibitors; D020169:Caspases