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.
Original language | English (US) |
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Pages (from-to) | 523-531 |
Number of pages | 9 |
Journal | Brain Research Bulletin |
Volume | 59 |
Issue number | 6 |
DOIs | |
State | Published - Feb 15 2003 |
Externally published | Yes |
Bibliographical note
Funding Information:This work was supported by a grant awarded by the National Institutes of Health (A. Y., MH59786-01) as well as an Alzheimer’s Association award (A. Y.). We express our special thanks to Drs. Starr Brennan, David Dunlop, Amos Neidle, and Henry Sershen for their excellent technical assistance and critical discussions concerning the content of this manuscript.