Aberrant induction of Par-4 is involved in apoptosis of hippocampal neurons in presenilin-1 M146V mutant knock-in mice.

Title

Aberrant induction of Par-4 is involved in apoptosis of hippocampal neurons in presenilin-1 M146V mutant knock-in mice.

Creator

Xie J; Chang X; Zhang X; Guo Q

Publisher

Brain research

Date

2001
2001-10

Description

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.

Subject

*Intracellular Signaling Peptides and Proteins; Alzheimer Disease/*genetics/metabolism/physiopathology; Animals; Apoptosis Regulatory Proteins; Apoptosis/*genetics; Carrier Proteins/*genetics/metabolism; Caspases/metabolism; Gene Expression Regulation/physiology; Glucose/deficiency; Hippocampus/*metabolism/physiopathology; Membrane Proteins/*genetics; Mice; Mitochondria/metabolism/pathology; Mutation/*genetics; Neurons/*metabolism/pathology; Presenilin-1; Signal Transduction/genetics; Transgenic/genetics/metabolism

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

1–10

Issue

1

Volume

915

Citation

Xie J; Chang X; Zhang X; Guo Q, “Aberrant induction of Par-4 is involved in apoptosis of hippocampal neurons in presenilin-1 M146V mutant knock-in mice.,” NEOMED Bibliography Database, accessed May 5, 2021, https://neomed.omeka.net/items/show/3836.

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