LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer's disease.
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.
Majercak
John
J
Department of Alzheimer's Research, Merck & Co., Inc., West Point, PA 19486, USA.
Ray
William J
WJ
Espeseth
Amy
A
Simon
Adam
A
Shi
Xiao-Ping
XP
Wolffe
Carrie
C
Getty
Krista
K
Marine
Shane
S
Stec
Erica
E
Ferrer
Marc
M
Strulovici
Berta
B
Bartz
Steven
S
Gates
Adam
A
Xu
Min
M
Huang
Qian
Q
Ma
Lei
L
Shughrue
Paul
P
Burchard
Julja
J
Colussi
Dennis
D
Pietrak
Beth
B
Kahana
Jason
J
Beher
Dirk
D
Rosahl
Thomas
T
Shearman
Mark
M
Hazuda
Daria
D
Sachs
Alan B
AB
Koblan
Kenneth S
KS
Seabrook
Guy R
GR
Stone
David J
DJ
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
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