title: Familial Alzheimer's disease mutations in presenilin 1 do not alter levels of the secreted amyloid-beta protein precursor generated by beta-secretase cleavage.
abstract: Alzheimer's disease (AD) is an insidious and progressive disease with a genetically complex and heterogenous etiology. More than 200 fully penetrant mutations in the amyloid beta-protein precursor (APP), presenilin 1 (or PSEN1), and presenilin 2 (PSEN2) have been linked to early-onset familial AD (FAD). 177 PSEN1 FAD mutations have been identified so far and account for more than approximately 80% of all FAD mutations. All PSEN1 FAD mutations can increase the Abeta42:Abeta40 ratio with seemingly different and incompletely understood mechanisms. A recent study has shown that the 286 amino acid N-terminal fragment of APP (N-APP), a proteolytic product of beta-secretase-derived secreted form of APP (sAPPbeta), could bind the death receptor, DR6, and lead to neurodegeneration. Here we asked whether PSEN1 FAD mutations lead to neurodegeneration by modulating sAPPbeta levels. All four different PSEN1 FAD mutations tested (in three mammalian cell lines) did not alter sAPPbeta levels. Therefore PS1 mutations do not appear to contribute to AD pathogenesis via altered production of sAPPbeta.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129-2060, USA. Zhang.Can@mgh.harvard.edu
authors.forename: Can
authors.initials: C
authors.lastname: Zhang
authors.forename: Andrew
authors.initials: A
authors.lastname: Browne
authors.forename: Doo Yeon
authors.initials: DY
authors.lastname: Kim
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004252:DNA Mutational Analysis; D006801:Humans; D051379:Mice; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases