Alzheimer's disease-associated presenilins 1 and 2: accelerated amyloid fibril formation of mutant 410 Cys-->Tyr and 141 Asn-->Ile peptides.

Mutations in the presenilin 1 gene on chromosome 14 and in the related gene on chromosome 1 have been identified in individuals with early-onset familial Alzheimer's disease. The functions of the presenilin gene products as well as the relation of the presenilin mutations to amyloidogenesis are unclear. Here we show that peptides homologous to two disease-associated mutant forms of presenilin 1 and 2, respectively, show highly increased amyloid fibril formation as compared with the wild-type peptide homologues. The 410 Cys -->Tyr (S-182) 14-residue peptide and the 141 Asn-->Ile (E5-1) 15-residue peptide spontaneously assemble to fibrils of 7 to 9 nm width with strong Congophilic characteristics. Thioflavine-T fluorometry reveals a 7- to 18-fold higher rate of amyloid fibril formation of the mutant peptides as compared with the corresponding wild-type homologues. The results provide new insights into the mechanisms by which presenilin mutations lead to Alzheimer-type neuropathology: missense mutations in the presenilin genes may create products that are intrinsically highly amyloidogenic and directly involved in pathogenesis.