Polymorphic C-terminal beta-sheet interactions determine the formation of fibril or amyloid beta-derived diffusible ligand-like globulomer for the Alzheimer Abeta42 dodecamer.

The relationship between amyloid deposition and cellular toxicity is still controversial. In addition to fibril-forming oligomers, other soluble Aß forms (amyloid ß-derived diffusible ligands (ADDLs)) were also suggested to form and to present different morphologies and mechanisms of toxicity. One ADDL type, the "globulomer," apparently forms independently of the fibril aggregation pathway. Even though many studies argue that such soluble Aß oligomers are off fibril formation pathways, they may nonetheless share some structural similarity with protofibrils. NMR data of globulomer intermediates, "preglobulomers," suggested parallel in-register C-terminal ß-sheets, with different N-terminal conformations. Based on experimental data, we computationally investigate four classes of Aß dodecamers: fibril, fibril oligomer, prefibril/preglobulomer cluster, and globulomer models. Our simulations of the solvent protection of double-layered fibril and globulomer models reproduce experimental observations. Using a single layer Aß fibril oligomer ß-sheet model, we found that the C-terminal ß-sheet in the fibril oligomer is mostly curved, preventing it from quickly forming a fibril and leading to its breaking into shorter pieces. The simulations also indicate that ß-sheets packed orthogonally could be the most stable species for Aß dodecamers. The major difference between fibril-forming oligomers and ADDL-like oligomers (globulomers) could be the exposure of Met-35 patches. Although the Met-35 patches are necessarily exposed in fibril-forming oligomers to allow their maturation into fibrils, the Met-35 patches in the globulomer are covered by other residues in the orthogonally packed Aß peptides. Our results call attention to the possible existence of certain "critical intermediates" that can lead to both seeds and other soluble ADDL-like oligomers.

Diagnostic criteria for the neuropathological assessment of Alzheimer's disease: current status and major issues.

A Consensus Conference focusing on Alzheimer's disease (AD) took place in November 1996 to recommend uniform evaluation procedures and diagnostic criteria, co-sponsored by the National Institute on Aging and the Reagan Institute of the Alzheimer's Association. In conjunction with this conference, we reviewed diagnostic practices in current use, together with various neuropathological criteria proposed since 1985. Difficulties were identified in developing "gold standard" criteria for diagnosis and case classification of AD based upon the current state of knowledge. Working criteria for use within research contexts were proposed that acknowledged the realities of scientific limitations by inclusion of a broad and heterogeneous category of "uncertain" cases. (Eventually, methods will be developed for identifying these cases as preclinical AD, dementia due to multiple causes or non-AD, but this is not now possible.) Within applied contexts, the use of CERAD guidelines was supported. Finally, recommendations generated at the Consensus Conference were discussed, emphasizing the rapid pace of recent scientific advancement and the need for ongoing empirical reevaluation and modification of the Group's proposal.