Calpain Activation in Alzheimer's Model Mice Is an Artifact of APP and Presenilin Overexpression.
J Neurosci
; 36(38): 9933-6, 2016 09 21.
Article
em En
| MEDLINE
| ID: mdl-27656030
ABSTRACT
UNLABELLED Intraneuronal calcium stimulates the calpain-dependent conversion of p35 to p25, a CDK5 activator. It is widely believed that amyloid ß peptide (Aß) induces this conversion that, in turn, has an essential role in Alzheimer's disease pathogenesis. However, in vivo studies on p25 generation used transgenic mice overexpressing mutant amyloid precursor protein (APP) and presenilin (PS). Here, using single App knock-in mice, we show that p25 generation is an artifact caused by membrane protein overexpression. We show that massive Aß42 accumulation without overexpression of APP or presenilin does not produce p25, whereas p25 generation occurred with APP/PS overexpression and in postmortem mouse brain. We further support this finding using mice deficient for calpastatin, the sole calpain-specific inhibitor protein. Thus, the intracerebral environment of the APP/PS mouse brain and postmortem brain is an unphysiological state. SIGNIFICANCE STATEMENT We recently estimated using single App knock-in mice that accumulate amyloid ß peptide without transgene overexpression that 60% of the phenotypes observed in Alzheimer's model mice overexpressing mutant amyloid precursor protein (APP) or APP and presenilin are artifacts (Saito et al., 2014). The current study further supports this estimate by invalidating key results from papers that were published in Cell These findings suggest that more than 3000 publications based on APP and APP/PS overexpression must be reevaluated.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Encéfalo
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Proteínas de Ligação ao Cálcio
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Precursor de Proteína beta-Amiloide
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Presenilina-1
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Doença de Alzheimer
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Neurosci
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Japão