Simvastatin enhances learning and memory independent of amyloid load in mice.
OBJECTIVE
Normal aging is often associated with a decline in learning and memory functions. This decline is manifested to a much greater extent in Alzheimer's disease. Recent studies have indicated statins, a class of cholesterol-lowering drugs, as a potential therapy for Alzheimer's disease. Our objective was to determine whether administering a statin drug (simvastatin) would protect against the development of behavioral deficits in an established mouse model of Alzheimer's disease.


METHODS
Tg2576 mice and their nontransgenic littermates were treated with simvastatin and assessed by behavioral tests and biochemical analyses.


RESULTS
Simvastatin treatment not only reversed learning and memory deficits in the Tg2576 mice, but also enhanced learning and memory in the nontransgenic mice. Moreover, levels of amyloid beta protein in the brains of treated mice did not differ from those of untreated mice. Simvastatin treatment was associated with increased expression levels of protein kinase B (Akt) and endothelial nitric oxide synthase in the mouse brain.


CONCLUSIONS
Our findings demonstrate that the effects of simvastatin on learning and memory are independent of amyloid beta protein levels. The mechanisms by which simvastatin exerts its beneficial effects may be related to modulation of signaling pathways in memory formation.
Li
Ling
L
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. lili@uab.edu
Cao
Dongfeng
D
Kim
Helen
H
Lester
Robin
R
Fukuchi
Ken-Ichiro
K
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002784:Cholesterol / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D007858:Learning / Q000187:drug effects / Q000502:physiology; D007859:Learning Disabilities / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism; D058225:Plaque, Amyloid / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
D000924:Anticholesteremic Agents; D018696:Neuroprotective Agents; D002784:Cholesterol; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt