An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (βAPP717) mutants

Nobuhiro Suzuki, Tobun T. Cheung, Xiao Dan Cai, Asano Odaka, Laszlo Otvos, Christopher Eckman, Todd E. Golde, Steven G. Younkin

Research output: Contribution to journalArticle

1293 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1336-1340
Number of pages5
JournalScience
Volume264
Issue number5163
DOIs
StatePublished - Jan 1 1994

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