Cellular mechanisms of beta-amyloid production and secretion

The major constituent of senile plaques in Alzheimer's disease is a 42-aa p eptide, referred to as beta-amyloid (A beta), A beta is generated from a fa mily of differentially spliced, type-1 transmembrane domain (TM)-containing proteins, called APP, by endoproteolytic processing. The major, relatively ubiquitous pathway of APP metabolism in cell culture involves cleavage by alpha-secretase, which cleaves within the A beta sequence, thus precluding A beta formation and deposition, An alternate secretory pathway, enriched i n neurons and brain, leads to cleavage of APP at the N terminus of the A be ta peptide by beta-secretase, thus generating a cell-associated beta-C-term inal fragment (beta-CTF). A pathogenic mutation at codons 670/671 in APP (A PP "Swedish") leads to enhanced cleavage at the beta-secretase scissile bon d and increased A beta formation. An inhibitor of vacuolar ATPases, bafilom ycin, selectively inhibits the action of beta-secretase in cell culture, su ggesting a requirement for an acidic intracellular compartment for effectiv e beta-secretase cleavage of APP, beta-CTF is cleaved in the TM domain by g amma-secretase(s), generating both A beta 1-40 (90%) and AP 1-42 (10%), Pat hogenic mutations in APP at codon 717 (APP "London") lead to an increased p roportion of A beta 1-42 being produced and secreted. Missense mutations in PS-1, localized to chromosome 14, are pathogenic in the majority of famili al 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 transgenic animals le ads to significant inhibition of production of both A beta 1-40 and A beta 1-42 in primary cultures, indicating that PS-1 expression is important for gamma-secretase cleavages, Peptide aldehyde inhibitors that block A beta pr oduction by inhibiting g-secretase cleavage of beta-CTF have been discovere d.