Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Abeta peptide in Alzheimer's disease (AD). Here we show that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers is inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of soluble amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.

Memory function often declines with age, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-beta precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-beta protein amyloidosis. Young Tg2576 mice (< 6 months old) have normal memory and lack neuropathology, middle-aged mice (6-14 months old) develop memory deficits without neuronal loss, and old mice (> 14 months old) form abundant neuritic plaques containing amyloid-beta (refs 3-6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-beta assembly, which we term Abeta*56 (Abeta star 56). Abeta*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Abeta*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.

Alzheimer's disease (AD) involves amyloid ␤ (A␤) accumulation, oxidative damage, and inflammation, and risk is reduced with increased antioxidant and antiinflammatory consumption. The phenolic yellow curry pigment curcumin has potent anti-inflammatory and antioxidant activities and can suppress oxidative damage, inflammation, cognitive deficits, and amyloid accumulation. Since the molecular structure of curcumin suggested potential A␤ binding, we investigated whether its efficacy in AD models could be explained by effects on A␤ aggregation. Under aggregating conditions in vitro, curcumin inhibited aggregation (IC 50 ‫؍‬ 0.8 M) as well as disaggregated fibrillar A␤40 (IC 50 ‫؍‬ 1 M), indicating favorable stoichiometry for inhibition. Curcumin was a better A␤40 aggregation inhibitor than ibuprofen and naproxen, and prevented A␤42 oligomer formation and toxicity between 0.1 and 1.0 M. Under EM, curcumin decreased dose dependently A␤ fibril formation beginning with 0.125 M. The effects of curcumin did not depend on A␤ sequence but on fibril-related conformation. AD and Tg2576 mice brain sections incubated with curcumin revealed preferential labeling of amyloid plaques. In vivo studies showed that curcumin injected peripherally into aged Tg mice crossed the blood-brain barrier and bound plaques. When fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin labeled plaques and reduced amyloid levels and plaque burden. Hence, curcumin directly binds small ␤-amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates A␤ as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clinical trials preventing or treating AD.The 4-kDa (40 -42-amino acid) amyloid-␤ peptide (A␤) 1 is derived from the amyloid precursor protein (APP) through sequential proteolysis by the aspartyl protease ␤-secretase and presenilin-dependent ␥-secretase cleavage (1). Mutations at the cleavage sites in APP or in presenilin that increase production or aggregation of A␤ provide a compelling argument for a central role for A␤ aggregation in the pathogenesis of Alzheimer's disease (AD). The progressive accumulation of A␤ aggregates is widely believed to be fundamental to the initial development of neurodegenerative pathology and to trigger a cascade of events such as neurotoxicity, oxidative damage, and inflammation that contribute to the progression of AD (2-5). Therefore, many therapeutic efforts are targeted at reducing A␤ production, including inhibiting secretase, increasing A␤ clearance with amyloid vaccines, or blocking A␤ aggregation (with antibodies, peptides, or small organic molecules that selectively bind and inhibit A␤ aggregate and fibril formation).A␤ fibrillization involves formation of dimers and small oligomers followed by growth into protofibrils and fibrils via a complex multistep-nucleated polymerization. Polymerizing A␤ fibrils and intermediates can be stained by amyloidophilic dyes such as Cong...

The progressive neurodegeneration of Alzheimer's disease has been hypothesized to be mediated, at least in part, by beta-amyloid protein. A relationship between the aggregation state of beta-amyloid protein and its ability to promote degeneration in vitro has been previously suggested. To evaluate this hypothesis and to define a structure-activity relationship for beta-amyloid, aggregation properties of an overlapping series of synthetic beta-amyloid peptides (beta APs) were investigated and compared with beta AP neurotoxic properties in vitro. Using light microscopy, electrophoresis, and ultracentrifugation assays, we found that few beta APs assembled into aggregates immediately after solubilization, but that over time peptides containing the highly hydrophobic beta 29-35 region formed stable aggregations. In short-term neuronal cultures, toxicity was associated specifically with those beta APs that also exhibited significant aggregation. Further, upon the partial reversal of beta 1-42 aggregation, a concomitant loss of toxicity was observed. A synthetic peptide derived from a different amyloidogenic protein, islet amyloid polypeptide, exhibited aggregation but not toxicity, suggesting that beta AP-induced neurotoxicity in vitro is not a nonspecific reaction to aggregated protein. The correlation between beta AP aggregation and neurotoxicity was also observed in long-term neuronal cultures but not in astrocyte cultures. These data are consistent with the hypothesis that beta-amyloid protein contributes to neurodegeneration in Alzheimer's disease.