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.
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 .
Which disease the London mutation involved in?
Which disease the London mutation involved in ?
Alzheimer's Disease
Alzheimer's Disease AD