Dual effects of statins on Aβ metabolism: upregulation of the degradation of APP-CTF and Aβ clearance.
OBJECTIVE
Retrospective cohort studies have suggested that statin users have a lower prevalence of dementia. On the other hand, a randomized controlled study failed to show beneficial effects on the cognitive decline in Alzheimer's disease (AD). However, a prospective cohort study demonstrated that users of statins had a lower incidence of AD. One possible interpretation might be that statins could prevent or delay the onset of AD, but not slow cognitive decline once the disease has set in. Given that statins could prevent or delay the onset of AD, what is the responsible mechanism?


METHODS
We investigated the effect of fluvastatin on Aβ metabolism at a clinically relevant dose in mice.


RESULTS
Fluvastatin reduced the brain Aβ level by increased trafficking of the carboxyl terminal fragment of the amyloid precursor protein (APP-CTF), which was mediated by inhibition of protein isoprenylation. Moreover, the statin reduced the brain Aβ level through enhanced Aβ clearance mediated by upregulation of low-density lipoprotein receptor-related protein 1 (LRP-1) expression. The statin increased LRP-1 expression, mediated by inhibition of protein isoprenylation.


CONCLUSIONS
Statins might prevent the onset of AD through reduced Aβ production by enhancement of APP-CTF degradation and/or upregulation of Aβ clearance. We also showed that promotion of APP-CTF degradation and upregulation of Aβ clearance could be modified by a drug, suggesting possible mechanistic targets for disease-modifying drugs.
Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Suita, Japan. nsato@cgt.med.osaka-u.ac.jp
Naoyuki
N
Sato
Mitsuru
M
Shinohara
Hiromi
H
Rakugi
Ryuichi
R
Morishita
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D015854:Up-Regulation / Q000187:drug effects*
D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors