title: Simvastatin treatment preserves synaptic plasticity in AβPPswe/PS1dE9 mice.
abstract: Epidemiological evidence suggests that chronic treatment with simvastatin may protect against the development of Alzheimer's disease (AD), but as yet it is unclear how this effect is mediated. Extensive data also indicates that the amyloid β-protein (Aβ) plays a central role in the disease process, and it has been suggested that the protective effects of simvastatin may be mediated by reducing Aβ production or by counteracting the toxic effects of Aβ. Accordingly, using the AβPPswe/PS1dE9 mouse model of AD, we investigated the effects of simvastatin on long-term potentiation (LTP), amyloid biology, and two key kinases involved in Aβ-mediated toxicity. Since burgeoning data indicate that both fibrillar and non-fibrillar forms of Aβ play a prominent role in AD pathogenesis, we were careful to investigate the effects of simvastatin on three biochemically distinct pools of Aβ. In untreated AβPPswe/PS1dE9 mice, there was a dramatic and significant increase in the levels of water-soluble Aβ between 6 and 8 months, but this remained constant between 8 and 18 months. In contrast, the concentrations of detergent-soluble and formic acid (FA)-soluble Aβ species increased across all ages examined, thus demonstrating that while amyloid deposition continued, the levels of water-soluble Aβ remained relatively constant. LTP was normal at 6 months, but was significantly impaired at 8 and 18 months. Importantly, a diet supplemented with 0.04% simvastatin for one month (at 7 months) positively affected synaptic plasticity in AβPPswe/PS1dE9 mice and did not significantly alter levels of water-soluble, detergent-soluble, or FA-soluble Aβ, but did increase phosphorylation of both Akt and GSK-3, while tau and tau phosphorylation were unaltered. These results indicate that the protective effects of simvastatin may be mediated by maintaining signaling pathways that help to protect and rescue LTP.
authors.affiliation: School of Biomolecular and Biomedical Sciences, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Charles
authors.initials: C
authors.lastname: Métais
authors.affiliation: School of Biomolecular and Biomedical Sciences, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Brennan
authors.affiliation: School of Biomolecular and Biomedical Sciences, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Mably
authors.affiliation: School of Biomolecular and Biomedical Sciences, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: Scott
authors.affiliation: School of Biomolecular and Biomedical Sciences, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
authors.affiliation: School of Biomolecular and Biomedical Sciences, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Herron
mesh_terms: D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000187:drug effects*; D018697:Nootropic Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D053764:Presenilin-1 / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C558298:Mapt protein, mouse; D018697:Nootropic Agents; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins; D019821:Simvastatin; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: Alzheimer's disease; amyloid-β; hippocampus; long-term potentiation; statin