Simvastatin treatment preserves synaptic plasticity in AßPPswe/PS1dE9 mice.
J Alzheimers Dis
; 39(2): 315-29, 2014.
Article
em En
| MEDLINE
| ID: mdl-24164738
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 ß-protein (Aß) plays a central role in the disease process, and it has been suggested that the protective effects of simvastatin may be mediated by reducing Aß production or by counteracting the toxic effects of Aß. Accordingly, using the AßPPswe/PS1dE9 mouse model of AD, we investigated the effects of simvastatin on long-term potentiation (LTP), amyloid biology, and two key kinases involved in Aß-mediated toxicity. Since burgeoning data indicate that both fibrillar and non-fibrillar forms of Aß play a prominent role in AD pathogenesis, we were careful to investigate the effects of simvastatin on three biochemically distinct pools of Aß. In untreated AßPPswe/PS1dE9 mice, there was a dramatic and significant increase in the levels of water-soluble Aß 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 Aß species increased across all ages examined, thus demonstrating that while amyloid deposition continued, the levels of water-soluble Aß 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 AßPPswe/PS1dE9 mice and did not significantly alter levels of water-soluble, detergent-soluble, or FA-soluble Aß, 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.
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Base de dados:
MEDLINE
Assunto principal:
Sinapses
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Nootrópicos
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Sinvastatina
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Plasticidade Neuronal
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article