title: APH1, PEN2, and Nicastrin increase Abeta levels and gamma-secretase activity.
abstract: A major component of the amyloid plaque core in Alzheimer's disease (AD) is the 40-42-residue amyloid beta peptide (Abeta). Mutations linked to AD such as those in presenilins 1 (PS1) and 2 (PS2) invariably increase the longer Abeta42 species that forms neurotoxic oligomers. It is believed that PS1/2 constitute the catalytic subunit of the gamma-secretase responsible for the final step in Abeta biogenesis. Recent genetic studies have identified a number of additional genes encoding APH1a, APH1b, PEN2, and Nicastrin proteins, which are part of the gamma-secretase complex with PS1. Further, knockout studies using RNAi showed that these components are essential for gamma-secretase activity. However, the nature of gamma-secretase and how the aforementioned proteins regulate its activity are still incompletely understood. Here we present evidence that unlike PS1, overexpression of these proteins can increase the levels of Abeta, suggesting that these proteins are limiting for gamma-secretase activity. In addition, our studies also suggest that the presenilin partners regulate the relative levels of Abeta40 and Abeta42.
authors.affiliation: Department of Physiology and Neuroscience, Medical University of South Carolina, 173 Ashley Avenue, Suite 403, Charleston, SC 29425, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Marlow
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Canet
authors.forename: Sharie J
authors.initials: SJ
authors.lastname: Haugabook
authors.forename: John A
authors.initials: JA
authors.lastname: Hardy
authors.forename: Debomoy K
authors.initials: DK
authors.lastname: Lahiri
authors.forename: Kumar
authors.initials: K
authors.lastname: Sambamurti
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D008954:Models, Biological; D010446:Peptide Fragments / Q000096:biosynthesis*; D010447:Peptide Hydrolases; D053764:Presenilin-1; D021122:Protein Subunits
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C437330:CTFgamma protein, rat; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C469349:PSENEN protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D021122:Protein Subunits; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C413604:nicastrin protein; C475154:APH1A protein, human; C475155:APH1B protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human