Abstract

Aggregates of Aβ peptides and tau protein are defining features of Alzheimer's disease (AD) but the contribution of these structures to the etiology of disease remains uncertain. High resolution structures of fibrillar polymorphs have provided a basis for studies of disease, but fall short of defining the molecular mechanisms underlying disease progression. Evidence is accumulating that the peptide conformation within fibrils correlates with disease subtype and suggests that protofilament conformation represents the physical embodiment of a ‘strain’ of AD. Within a single strain the fold of peptides may be invariant. But the fibrils are capable of polymorphism that includes variation in the packing of protofilaments into fibrils; the pitch of the resultant fibrils and the higher order organization of plaques into which they aggregate. These intra-strain polymorphisms are divided 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 relevant toxic species, be they monomers, oligomers or higher order structures. To better understand their role in disease, in situ studies of fibril structure have been carried out on histological thin sections of human brain tissue. Scanning x-ray microdiffraction is providing information on the variation of fibrillar polymorphism at sub-cellular length scales and makes possible mapping the distribution of polymorphs within tissue. Scattering in the wide-angle regime produces information on fibrillar twist. Scattering in the small-angle regime can be used to generate the cross-sectional shape of fibrils. Mapping the variation of these structural parameters across and among plaques and tangles in different regions of the brain provides insight into the development and evolution of neurodegenerative lesions.

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