Alzheimer-associated neuronal thread protein-induced apoptosis and impaired mitochondrial function in human central nervous system-derived neuronal cells.
In Alzheimer Disease (AD), dementia is due to cell loss and impaired synaptic function. The cell loss is mediated by increased apoptosis, predisposition to apoptosis, and impaired mitochondrial function. Previous studies demonstrated that the AD7c-NTP neuronal thread protein gene is over-expressed in AD beginning early in the course of disease, and that in AD, AD7c-NTP protein accumulation in neurons co-localizes with phospho-tau-immunoreactivity. To determine the potential contribution of AD7c-NTP over-expression to cell loss in AD, we utilized an inducible mammalian expression system to regulate AD7c-NTP gene expression in human CNS-derived neuronal cells by stimulation with isopropyl-1-beta-D-thiogalactopyranoside (IPTG). IPTG induction of AD7c-NTP gene expression resulted in increased cell death mediated by apoptosis, impaired mitochondrial function, and increased cellular levels of the p53 and CD95 pro-apoptosis gene products as occur in AD. In addition, over-expression of AD7c-NTP was associated with increased levels of phospho-tau, but not amyloid-beta immunoreactivity. These results suggest that AD7c-NTP over-expression may have a direct role in mediating some of the important cell death cascades associated with AD neurodegeneration, and further establish a link between AD7c-NTP overexpression and the accumulation of phospho-tau in preapoptotic CNS neuronal cells.
de la Monte
S M
SM
Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence 02903, USA.
Wands
J R
JR
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology
C109804:AD7c-NTP; D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins