The major constituent of senile plaques in Alzheimer's disease is a 42-aa 
peptide, referred to as beta-amyloid (Abeta). Abeta is generated from a family 
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 Abeta sequence, thus precluding Abeta formation and 
deposition. An alternate secretory pathway, enriched in neurons and brain, leads 
to cleavage of APP at the N terminus of the Abeta 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 Abeta 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 Abeta 1-40 
(90%) and Abeta 1-42 (10%). Pathogenic mutations in APP at codon 717 (APP 
"London") lead to an increased proportion of Abeta 1-42 being produced and 
secreted. Missense mutations in PS-1, localized to chromosome 14, are pathogenic 
in the majority of familial Alzheimer's pedigrees. These mutations also lead to 
increased production of Abeta 1-42 over Abeta 1-40. Knockout of PS-1 in 
transgenic animals leads to significant inhibition of production of both Abeta 
1-40 and Abeta 1-42 in primary cultures, indicating that PS-1 expression is 
important for gamma-secretase cleavages. Peptide aldehyde inhibitors that block 
Abeta production by inhibiting gamma-secretase cleavage of beta-CTF have been 
discovered.