Statins stimulate alpha-secretase cleavage of APP
Kofi
Statin's excitoprotection is mediated by sAPP and the subsequent
attenuation of calpain-induced truncation events, likely via rho-ROCK
signaling.
Ma T, Zhao Y, Kwak YD, Yang Z, Thompson R, Luo Z, Xu H, Liao FF.
Department of Pharmacology, University of Tennessee Health Science
Center, College of Medicine, Memphis, Tennessee 38163, USA.
The widely used cholesterol-lowering drugs, statins, were reported to
reduce the incidence of stroke and the progression of Alzheimer's
disease. However, little is known on how statins exert these beneficial
effects. In this study, we investigated the molecular mechanisms
underlying the neuroprotective actions of statins in primary cultured
cortical neurons. We found that chronic treatment of neurons with a low
dosage of two CNS-permeable statins (lovastatin and simvastatin)
selectively reduced NMDA-induced cell death but not the caspase-mediated
apoptosis. The protective effects of stains were inhibited by
mevalonate, a PI3K inhibitor, and tyrphostin AG538, suggesting roles for
cholesterol and insulin/IGF-1 signaling in the neurotoxic response. We
further demonstrate that statins block calcium-dependent calpain
activation, resulting in complete suppression of protein truncation
events on multiple calpain substrates that are involved in neuronal
death including CDK5 coactivator p35 cleavage to p25, GSK3 and
beta-catenin. This is followed by reduced and increased nuclear
translocation of p25 and beta-catenin, respectively. Under excitotoxic
conditions, the activities of CDK5 and beta-catenin are exclusively
regulated by calpain-mediated cleavage while apoptosis modulates
beta-catenin mainly through phosphorylation. Strikingly, our data
demonstrate that the calpain-blocking effect of statins is largely
mediated by stimulation of alpha-secretase cleavage of APP, resulting in
increased secretion of its soluble form, sAPP. Finally, our data suggest
that statin-regulated sAPP secretion occurs via activation of the PI3K
pathway and inhibition of ROCK signaling. Altogether, our study provides
novel insights into statin-mediated neuronal excitoprotection through
both cholesterol-dependent and -independent mechanisms and links them to
calpain-mediated neuronal death.
Publication Types:
* Comparative Study
* Research Support, N.I.H., Extramural
* Research Support, Non-U.S. Gov't
PMID: 19741129