The Structural Basis of Amyloid Strains in Alzheimer’s Disease

Amyloid fibrils represent one of the defining features of Alzheimer's disease (AD). They are made up of protofilaments composed of amyloid β (Aβ) peptides that are held together with extraordinary stability by a network of tight steric zippers and axial hydrogen bonds. This review explores the hypothesis that the peptide conformation within a protofilament represents the physical embodiment of a "strain" of AD. Evidence suggests that within a single strain the fold of individual peptides is invariant. However, the fibrils are capable of structural polymorphism that includes variation in the arrangement of protofilaments into fibrils, the pitch of the resultant fibrils, and the higher-order organization of the plaques into which they aggregate. These intrastrain polymorphisms are separated by low energy barriers, allowing multiple configurations to coexist within a single preparation or tissue. Clinical presentation of different strains may be determined by variation in the way different protofilament structures generate the relevant toxic species, be they monomers, oligomers, or higher-order structures. Evidence reviewed here is consistent with a model in which disease progression is concomitant with a gradual, progressive annealing of amyloid fibrils from benign, loosely packed structures into dense neurotoxic aggregates. This model challenges the commonly held hypothesis that oligomers of Aβ peptides are the only active proximate species in neurodegeneration. However, the data do not implicate fibrils themselves. Rather, they cast suspicion on larger-scale supramolecular aggregates as toxic agents. Electron tomography of amyloid plaques in situ strongly suggests that the formation of amyloid aggregates results in perturbation of the cellular membrane integrity, warranting further investigation of this as a potential mode of neurotoxicity. If dense supramolecular amyloid aggregates prove to be important agents of neurodegeneration in AD, this model may also have relevance to other forms of amyloidoses.