title: Aberrant induction of Par-4 is involved in apoptosis of hippocampal neurons in presenilin-1 M146V mutant knock-in mice.
abstract: Mutations in presenilin-1 (PS-1) have been shown to increase neuronal vulnerability to apoptosis in Alzheimer's disease (AD). Par-4 is a novel cell-death-promoting protein associated with neuronal degeneration in AD. We previously reported that, in transfected PC12 cells, Par-4 seems to be involved in the neurodegenerative mechanisms of PS-1 mutations. However, direct evidence for a necessary role of Par-4 in the pathogenic mechanisms of PS-1 mutations in neurons is lacking. We recently generated and characterized presenilin-1 mutant M146V knock-in (PS-1 M146V KI) mice. We now report that expression of the mutant presenilin-1 in these mice induces early and exaggerated increase in Par-4 expression in hippocampal neurons following glucose deprivation (an insult relevant to the pathogenesis of AD). Importantly, inhibition of Par-4 expression by antisense par-4 oligonucleotide treatment counteracts neuronal apoptosis promoted by M146V mutation of PS-1. Mitochondrial dysfunction and caspase-3 activity induced by glucose deprivation was significantly exacerbated in hippocampal neurons expressing the mutant PS-1. Antisense par-4 treatment largely suppressed the adverse effect of the mutant PS-1 on mitochondrial dysfunction and caspase activation. These results provide evidence in hippocampal neurons that Par-4 is involved in the neurodegenerative cascades associated with PS-1 M146V mutation by acting relatively early in the apoptotic process before mitochondrial dysfunction and caspase-3 activation. Since levels of Par-4 are significantly increased in the hippocampus in human AD brain, the results of this study may provide a significant link between aberrant induction of Par-4 and the neurodegenerative cascades promoted by PS-1 mutations in AD.
authors.affiliation: Department of Neurobiology and Pharmacology, Northeastern Ohio Universities College of Medicine, 4209 State Route 44, P.O. Box 95, Rootstown, OH 44272-0095, USA.
authors.forename: J
authors.initials: J
authors.lastname: Xie
authors.forename: X
authors.initials: X
authors.lastname: Chang
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: Q
authors.initials: Q
authors.lastname: Guo
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D053764:Presenilin-1; D015398:Signal Transduction / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; C101296:prostate apoptosis response-4 protein; D020169:Caspases; D005947:Glucose