Journal
JOURNAL OF NEUROSCIENCE
Volume 36, Issue 38, Pages 9933-9936Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1907-16.2016
Keywords
amyloid; calpain; Na(v)1.1; p25
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Japan Science and Technology Agency Precursory Research for Embryonic Science and Technology
- Brain Mapping by Integrated Neurotechnologies for Disease Studies project of the Japan Agency for Medical Research and Development
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Intraneuronal calcium stimulates the calpain-dependent conversion of p35 to p25, a CDK5 activator. It is widely believed that amyloid beta peptide (A beta) 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 A beta(42) 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.
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