title: Age-dependent rescue by simvastatin of Alzheimer's disease cerebrovascular and memory deficits.
abstract: Alzheimer's disease (AD) is now established as a progressive compromise not only of the neurons but also of the cerebral vasculature. Increasing evidence also indicates that cerebrovascular dysfunction may be a key or an aggravating pathogenic factor in AD, emphasizing the importance to properly control this deficit when aiming for effective therapy. Here, we report that simvastatin (3-6 months, 40 mg/kg/d) completely rescued cerebrovascular reactivity, basal endothelial nitric oxide synthesis, and activity-induced neurometabolic and neurovascular coupling in adult (6 months) and aged (12 months) transgenic mice overexpressing the Swedish and Indiana mutations of the human amyloid precursor protein (AD mice). Remarkably, simvastatin fully restored short- and long-term memory in adult, but not in aged AD mice. These beneficial effects occurred without any decreasing effect of simvastatin on brain amyloid-β (Aβ) levels or plaque load. However, in AD mice with recovered memory, protein levels of the learning- and memory-related immediate early genes c-Fos and Egr-1 were normalized or upregulated in hippocampal CA1 neurons, indicative of restored neuronal function. In contrast, the levels of phospholipase A2, enkephalin, PSD-95, synaptophysin, or glutamate NMDA receptor subunit type 2B were either unaltered in AD mice or unaffected by treatment. These findings disclose new sites of action for statins against Aβ-induced neuronal and cerebrovascular deficits that could be predictive of therapeutic benefit in AD patients. They further indicate that simvastatin and, possibly, other brain penetrant statins bear high therapeutic promise in early AD and in patients with vascular diseases who are at risk of developing AD.
authors.affiliation: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Québec H3A 2B4, Canada.
authors.forename: Xin-Kang
authors.initials: XK
authors.lastname: Tong
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lecrux
authors.forename: Pedro
authors.initials: P
authors.lastname: Rosa-Neto
authors.forename: Edith
authors.initials: E
authors.lastname: Hamel
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000502:physiology; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D019821:Simvastatin