title: Selective benefits of simvastatin in bitransgenic APPSwe,Ind/TGF-β1 mice.
abstract: Cognitive and cerebrovascular deficits are 2 landmarks of Alzheimer's disease (AD) to target for effective therapy. Here, we evaluated the efficacy of simvastatin in bitransgenic A/T mice overexpressing a mutated form of the human amyloid precursor protein (APP(Swe,Ind)) and a constitutively active form of transforming growth factor-β1. These mice feature the AD amyloid beta (Aβ) and cerebrovascular pathology. Simvastatin significantly decreased insoluble Aβ peptide levels and Aβ plaque load despite no effect on β-site amyloid precursor protein-cleaving enzyme and Aβ-degrading enzyme neprilysin protein levels. However, simvastatin failed to improve spatial learning and memory deficits and the decreased baseline levels of the memory-related protein early growth response-1 (Egr-1) in the hippocampus CA1 area. The impaired hyperemic response to whisker stimulation in A/T mice was not improved with treatment, but simvastatin fully restored constitutive nitric oxide synthesis in vessel walls and exacerbated agonist-mediated dilatory deficits. These findings point to the efficacy of simvastatin on selective AD features in a complex model of the disease, likely reflecting the challenges faced by recent clinical trials in assessing statin efficacy.
authors: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors: Panayiota
authors: P
authors: Papadopoulos
authors: Xin-Kang
authors: XK
authors: Tong
authors: Edith
authors: E
authors: Hamel
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D007858:Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009154:Mutation; D009569:Nitric Oxide / Q000096:biosynthesis; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide; D019821:Simvastatin
keywords: Alzheimer's disease; Amyloidosis; Memory; PI3/Akt pathway; Simvastatin; Transforming growth factor-β1