Hybrid Amyloid Fibril Genesis with Components of Sporadic and Familial Alzheimer's Disease

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Generally, Alzheimer's Disease (AD) develops spontaneously. Nevertheless, many families with an inheritable occurrence were identified. Of these, a considerable number shows mutations in the Alzheimer Precursor Protein (APP) gene concerning regions of the As1-40 peptide, as e. g. the “Flemish” A21G [APP A692G] or the “Iowa” mutant D23N[APP D694N]. All except two of today's known As1-40 mutations in familial AD were reported heterozygously dominant. Therefore, an interaction of wild type (WT) and mutated (MUT) As peptide is likely to occur in the brain of affected patients.Here we report on the extended co-fibrillation analysis of WT and MUT As1-40 peptide. Thioflavin-T fluorescence data of cofibrillation kinetics indicated a collateral aggregation process, correlated with the MUT:WT ratio.Coherently, the fibril morphologies of cofibrillates as observed in negative contrast transmission electron micrographs also appear to correlate with the MUT:WT peptide ratio.We interpret these results that MUT peptide with a preferred fibril conformation can template the fibril formation of the morphologically pluripotent WT dose-dependently. This may explain the strain-like symptomatic of different familial AD cases.