Cellular mechanisms of #beta#-amyloid production and secretion

摘要

The major constituent of senile plaques in Alzheimer's disease is a 42-aa peptide, referred to as #beta#u-amy- loid (A#beta#). A#beta# is generated from a family of differentially spliced, type-1 transmembrane domain (TM)-containing pro- teins, called APP, by endoproteolytic processing. The major, relatively ubiquitous pathway of APP metabolism in cell culture involves cleavage by #aipha#-secretase, which cleaves within the A#beta# sequence, thus precluding A#beta# formation and deposi- tion. An alternate secretory pathway, enriched in neurons and brain, leads to cleavage of APP at the N terminus of the A#beta# peptide by #beta#-secretase, thus generating a cell-associated #beta#-C- terminal fragment (#beta#-CTF). A pathogenic mutation at codons 670/671 in APP (APP "Swedish") leads to enhanced cleavage at the #beta#-secretase scissile bond and increased A#beta# formation. An inhibitor of vacuolar ATPases, bafilomycin, selectively inhibits the action of #beta#-secretase in cell culture, suggesting a requirement for an acidic intracellular compartment for effective #beta#-secretase cleavage of APP. #beta#-CTF is cleaved in the TM domain by #gamma#-secretase(s),generating both A#beta#1-409(90) and A#beta# 1-42 (10). Pathogenic mutations in APP at codon 717 (APP "London") lead to an increased proportion of A#beta# l-42 being produced and secreted. Missense mutations in PS-l, localized to chromosome 14, are pathogenic in the majority of familial Alzheimer's pedigrees. These mutations also lead to increased production of A#beta# 1-42 over A#beta# 1-40. Knockout of PS-1 in trans