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Titolo:
Aberrant induction of Par-4 is involved in apoptosis of hippocampal neurons in presenilin-1 M146V mutant knock-in mice
Autore:
Xie, J; Chang, XW; Zhang, XJ; Guo, Q;
Indirizzi:
NE Ohio Univ, Coll Med, Dept Neurobiol & Pharmacol, Rootstown, OH 44272 USA NE Ohio Univ Rootstown OH USA 44272 & Pharmacol, Rootstown, OH 44272 USA
Titolo Testata:
BRAIN RESEARCH
fascicolo: 1, volume: 915, anno: 2001,
pagine: 1 - 10
SICI:
0006-8993(20011005)915:1<1:AIOPII>2.0.ZU;2-Z
Fonte:
ISI
Lingua:
ENG
Soggetto:
AMYLOID PRECURSOR PROTEIN; CAPACITATIVE CALCIUM-ENTRY; TROPHIC FACTOR WITHDRAWAL; GAMMA-SECRETASE ACTIVITY; ALZHEIMERS-DISEASE; BETA-PEPTIDE; GLUCOSE DEPRIVATION; INCREASED VULNERABILITY; CASPASE ACTIVATION; CELL-DEATH;
Keywords:
presenilin-1; Par-4; hippocampal neurons; knock-in mice;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
88
Recensione:
Indirizzi per estratti:
Indirizzo: Guo, Q NE Ohio Univ, Coll Med, Dept Neurobiol & Pharmacol, 4209 State Route 44,POB 95, Rootstown, OH 44272 USA NE Ohio Univ 4209 State Route 44,POB 95 Rootstown OH USA 44272 USA
Citazione:
J. Xie et al., "Aberrant induction of Par-4 is involved in apoptosis of hippocampal neurons in presenilin-1 M146V mutant knock-in mice", BRAIN RES, 915(1), 2001, pp. 1-10

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 PC 12 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-I 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 neurode generative 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 neurode generative cascades promoted by PS-1 mutations in AD. (C) 2001 Elsevier Science BY. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 03/04/20 alle ore 11:12:21