Simvastatin treatment preserves synaptic plasticity in AßPPswe/PS1dE9 mice.

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.

Human anti-Aß IgGs target conformational epitopes on synthetic dimer assemblies and the AD brain-derived peptide.

Soluble non-fibrillar assemblies of amyloid-beta (Aß) and aggregated tau protein are the proximate synaptotoxic species associated with Alzheimer's disease (AD). Anti-Aß immunotherapy is a promising and advanced therapeutic strategy, but the precise Aß species to target is not yet known. Previously, we and others have shown that natural human IgGs (NAbs) target diverse Aß conformers and have therapeutic potential. We now demonstrate that these antibodies bound with nM avidity to conformational epitopes on plate-immobilized synthetic Aß dimer assemblies, including synaptotoxic protofibrils, and targeted these conformers in solution. Importantly, NAbs also recognized Aß extracted from the water-soluble phase of human AD brain, including species that migrated on denaturing PAGE as SDS-stable dimers. The critical reliance on Aß's conformational state for NAb binding, and not a linear sequence epitope, was confirmed by the antibody's nM reactivity with plate-immobilized protofibrills, and weak uM binding to synthetic Aß monomers and peptide fragments. The antibody's lack of reactivity against a linear sequence epitope was confirmed by our ability to isolate anti-Aß NAbs from intravenous immunoglobulin using affinity matrices, immunoglobulin light chain fibrils and Cibacron blue, which had no sequence similarity with the peptide. These findings suggest that further investigations on the molecular basis and the therapeutic/diagnostic potential of anti-Aß NAbs are warranted.