Normal processing of the amyloid β protein precursor (βAPP) results in secretion of a soluble 4-kilodalton protein essentially identical to the amyloid β protein (Aβ) that forms insoluble fibrillar deposits in Alzheimer's disease. Human neuroblastoma (M17) cells transfected with constructs expressing wild-type βAPP or the βAPP717 mutants linked to familial Alzheimer's disease were compared by (i) isolation of metabolically labeled 4-kilodalton Aβ from conditioned medium, digestion with cyanogen bromide, and analysis of the carboxyl-terminal peptides released, or (ii) analysis of the Aβ in conditioned medium with sandwich enzyme-linked immunosorbent assays that discriminate Aβ1-40 from the longer Aβ1-42. Both methods demonstrated that the 4-kilodalton Aβ released from wild-type βAPP is primarily but not exclusively Aβ1-40. The βAPP717 mutations, which are located three residues carboxyl to Aβ43, consistently caused a 1.5- to 1.9-fold increase in the percentage of longer Aβ generated. Long Aβ (for example, Aβ1-42) forms insoluble amyloid fibrils more rapidly than Aβ1-40. Thus, the βAPP717 mutants may cause Alzheimer's disease because they secrete increased amounts of long Aβ, thereby fostering amyloid deposition.
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