title: LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's disease.
abstract: Rare familial forms of Alzheimer's disease (AD) are thought to be caused by elevated proteolytic production of the Abeta42 peptide from the beta-amyloid-precursor protein (APP). Although the pathogenesis of the more common late-onset AD (LOAD) is not understood, BACE1, the protease that cleaves APP to generate the N terminus of Abeta42, is more active in patients with LOAD, suggesting that increased amyloid production processing might also contribute to the sporadic disease. Using high-throughput siRNA screening technology, we assessed 15,200 genes for their role in Abeta42 secretion and identified leucine-rich repeat transmembrane 3 (LRRTM3) as a neuronal gene that promotes APP processing by BACE1. siRNAs targeting LRRTM3 inhibit the secretion of Abeta40, Abeta42, and sAPPbeta, the N-terminal APP fragment produced by BACE1 cleavage, from cultured cells and primary neurons by up to 60%, whereas overexpression increases Abeta secretion. LRRTM3 is expressed nearly exclusively in the nervous system, including regions affected during AD, such as the dentate gyrus. Furthermore, LRRTM3 maps to a region of chromosome 10 linked to both LOAD and elevated plasma Abeta42, and is structurally similar to a family of neuronal receptors that includes the NOGO receptor, an inhibitor of neuronal regeneration and APP processing. Thus, LRRTM3 is a functional and positional candidate gene for AD, and, given its receptor-like structure and restricted expression, a potential therapeutic target.
authors.affiliation: Department of Alzheimer's Research, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: John
authors.initials: J
authors.lastname: Majercak
authors.forename: William J
authors.initials: WJ
authors.lastname: Ray
authors.forename: Amy
authors.initials: A
authors.lastname: Espeseth
authors.forename: Adam
authors.initials: A
authors.lastname: Simon
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Shi
authors.forename: Carrie
authors.initials: C
authors.lastname: Wolffe
authors.forename: Krista
authors.initials: K
authors.lastname: Getty
authors.forename: Shane
authors.initials: S
authors.lastname: Marine
authors.forename: Erica
authors.initials: E
authors.lastname: Stec
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.forename: Berta
authors.initials: B
authors.lastname: Strulovici
authors.forename: Steven
authors.initials: S
authors.lastname: Bartz
authors.forename: Adam
authors.initials: A
authors.lastname: Gates
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.forename: Lei
authors.initials: L
authors.lastname: Ma
authors.forename: Paul
authors.initials: P
authors.lastname: Shughrue
authors.forename: Julja
authors.initials: J
authors.lastname: Burchard
authors.forename: Dennis
authors.initials: D
authors.lastname: Colussi
authors.forename: Beth
authors.initials: B
authors.lastname: Pietrak
authors.forename: Jason
authors.initials: J
authors.lastname: Kahana
authors.forename: Dirk
authors.initials: D
authors.lastname: Beher
authors.forename: Thomas
authors.initials: T
authors.lastname: Rosahl
authors.forename: Mark
authors.initials: M
authors.lastname: Shearman
authors.forename: Daria
authors.initials: D
authors.lastname: Hazuda
authors.forename: Alan B
authors.initials: AB
authors.lastname: Sachs
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Koblan
authors.forename: Guy R
authors.initials: GR
authors.lastname: Seabrook
authors.forename: David J
authors.initials: DJ
authors.lastname: Stone
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002879:Chromosomes, Human, Pair 10; D004789:Enzyme Activation; D006801:Humans; D000090263:Leucine-Rich Repeat Proteins; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; C517878:LRRTM3 protein, human; D000090263:Leucine-Rich Repeat Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011506:Proteins; D034741:RNA, Small Interfering; C465345:RUFY2 protein, human; D011956:Receptors, Cell Surface; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human