Now showing 1 - 3 of 3
  • Publication
    Amyloid-b nanotubes are associated with prion protein-dependent synaptotoxicity
    Growing evidence suggests water-soluble, non-fibrillar forms of amyloid-β protein (Aβ) have important roles in Alzheimer's disease with toxicities mimicked by synthetic Aβ(1-42). However, no defined toxic structures acting via specific receptors have been identified and roles of proposed receptors, such as prion protein (PrP), remain controversial. Here we quantify binding to PrP of Aβ(1-42) after different durations of aggregation. We show PrP-binding and PrP-dependent inhibition of long-term potentiation (LTP) correlate with the presence of protofibrils. Globular oligomers bind less avidly to PrP and do not inhibit LTP, whereas fibrils inhibit LTP in a PrP-independent manner. That only certain transient Aβ assemblies cause PrP-dependent toxicity explains conflicting reports regarding the involvement of PrP in Aβ-induced impairments. We show that these protofibrils contain a defined nanotubular structure with a previously unidentified triple helical conformation. Blocking the formation of Aβ nanotubes or their interaction with PrP might have a role in treatment of Alzheimer's disease.
    Scopus© Citations 105  298
  • Publication
    Simvastatin Treatment Preserves Synaptic Plasticity in AβPPswe/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 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.
    Scopus© Citations 20  529
  • Publication
    Amyloid β-Protein Dimers Rapidly Form Stable Synaptotoxic Protofibrils
    Nonfibrillar, water-soluble low-molecular weight assemblies of the amyloid beta-protein (A beta) are believed to play an important role in Alzheimer's disease (AD). Aqueous extracts of human brain contain A beta assemblies that migrate on SDS-polyacrylamide gels and elute from size exclusion as dimers (similar to 8 kDa) and can block long-term potentiation and impair memory consolidation in the rat. Such species are detected specifically and sensitively in extracts of Alzheimer brain suggesting that SDS-stable dimers may be the basic building blocks of AD-associated synaptotoxic assemblies. Consequently, understanding the structure and properties of A beta dimers is of great interest. In the absence of sufficient brain-derived dimer to facilitate biophysical analysis, we generated synthetic dimers designed to mimic the natural species. For this, A beta(1-40) containing cysteine in place of serine 26 was used to produce disulphide cross-linked dimer, (A beta S26C)(2). Such dimers had no detectable secondary structure, produced an analytical ultracentrifugation profile consistent for an similar to 8.6 kDa protein, and had no effect on hippocampal long-term potentiation (LTP). However, (A beta S26C)(2) aggregated more rapidly than either A beta S26C or wild-type monomers and formed parastable beta-sheet rich, thioflavin T-positive, protofibril-like assemblies. Whereas wildtype A beta aggregated to form typical amyloid fibrils, the protofibril-like structures formed by (A beta S26C)(2) persisted for prolonged periods and potently inhibited LIP in mouse hippocampus. These data support the idea that A beta dimers may stabilize the formation of fibril intermediates by a process distinct from that available to A beta monomer and that higher molecular weight prefibrillar assemblies are the proximate mediators of A beta toxicity.
    Scopus© Citations 210  272