title: Monogenic determinants of familial Alzheimer's disease: presenilin-1 mutations.
abstract: Presenilin-1 (PS1) mutations account for the greatest portion of early onset familial Alzheimer's disease (FAD) cases. The exact cellular function of PS1 is not known. To date, PS1 mutations have been shown to alter two potential biological roles of the protein, either of which could make neurons more susceptible to neurodegeneration. First, PS1 mutations result in elevated A beta 42/A beta 40 ratios in plasma of FAD patients, in transgenic mice and in transfected cell lines. A beta 42 is the more hydrophobic and most neurotoxic form of the peptide. A common molecular event that has been associated with all of the known early onset FAD genes is the excessive production or accumulation of the A beta peptide in the brain. PS1 mutations have also been found to alter the Notch signalling pathway, but the mechanism by which this may affect neurodegeneration remains to be determined. Future studies will be needed to elucidate whether PS1 mutations lead directly to neuronal dysfunction and degeneration or cause cell death by increasing A beta 42 generation and deposition.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Kovacs
authors.forename: R E
authors.initials: RE
authors.lastname: Tanzi
mesh_terms: D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D029742:Caenorhabditis elegans Proteins; D002460:Cell Line; D015870:Gene Expression; D015801:Helminth Proteins / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D053764:Presenilin-1; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C095907:SEL-12 protein, C elegans; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)