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Cellular Mechanisms of beta Amyloid Production and Secretion

Cellular Mechanisms of beta Amyloid Production and Secretion,10.1073/pnas.96.20.11049,Proceedings of The National Academy of Sciences,Sukanto Sinha,Iv

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Cellular Mechanisms of beta Amyloid Production and Secretion   (Citations: 97)
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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.
Journal: Proceedings of The National Academy of Sciences - PNAS , vol. 961, no. 20, pp. 11049-11053, 1999
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