Most cases of Alzheimer's disease (AD) are sporadic, while a small percentage of AD cases, called familial AD (FAD), are associated with mutations in presinilins 1 and 2 and the amyloid precursor protein (APP). APP mutations falling within the Aβ sequence lead to a wide range of disease phenotypes. There is increasing evidence that distinct amyloid structures distinguished by amyloid conformation-dependent monoclonal antibodies have varying roles in pathology. It is possible that the phenotypic diversity of FAD associated with mutations within the Aβ sequence is due to differences in the conformations adopted by mutant Aβ peptides. We investigated the effects of 11 FAD mutations on the aggregation kinetics of Aβ, as well as its ability to form distinct conformations recognized by a panel of amyloid conformation-specific monoclonal antibodies. We also studied the morphologies of the aggregates formed by Aβ containing these mutations using transmission electron microscopy (TEM). Most FAD mutations increased the rate of aggregation of Aβ. The FAD mutations also led to the adoption of alternative amyloid conformations distinguished by mOC antibodies and resulted in the formation of distinct aggregate morphologies. In addition, several of the mutant peptides displayed a large reduction in thioflavin T (ThT) fluorescence, despite forming abundant fibrils indicating that ThT is a probe of conformational polymorphisms rather than a reliable indicator of fibrillization. Taken together, these results indicate that FAD mutations falling within the Aβ sequence lead to dramatic changes in aggregation kinetics, as well as the ability of Aβ to form immunologically and morphologically distinct amyloid structures
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