title: LRRTM3 interacts with APP and BACE1 and has variants associating with late-onset Alzheimer's disease (LOAD).
abstract: Leucine rich repeat transmembrane protein 3 (LRRTM3) is member of a synaptic protein family. LRRTM3 is a nested gene within α-T catenin (CTNNA3) and resides at the linkage peak for late-onset Alzheimer's disease (LOAD) risk and plasma amyloid β (Aβ) levels. In-vitro knock-down of LRRTM3 was previously shown to decrease secreted Aβ, although the mechanism of this is unclear. In SH-SY5Y cells overexpressing APP and transiently transfected with LRRTM3 alone or with BACE1, we showed that LRRTM3 co-localizes with both APP and BACE1 in early endosomes, where BACE1 processing of APP occurs. Additionally, LRRTM3 co-localizes with APP in primary neuronal cultures from Tg2576 mice transduced with LRRTM3-expressing adeno-associated virus. Moreover, LRRTM3 co-immunoprecipitates with both endogenous APP and overexpressed BACE1, in HEK293T cells transfected with LRRTM3. SH-SY5Y cells with knock-down of LRRTM3 had lower BACE1 and higher CTNNA3 mRNA levels, but no change in APP. Brain mRNA levels of LRRTM3 showed significant correlations with BACE1, CTNNA3 and APP in ∼400 humans, but not in LRRTM3 knock-out mice. Finally, we assessed 69 single nucleotide polymorphisms (SNPs) within and flanking LRRTM3 in 1,567 LOADs and 2,082 controls and identified 8 SNPs within a linkage disequilibrium block encompassing 5'UTR-Intron 1 of LRRTM3 that formed multilocus genotypes (MLG) with suggestive global association with LOAD risk (p = 0.06), and significant individual MLGs. These 8 SNPs were genotyped in an independent series (1,258 LOADs and 718 controls) and had significant global and individual MLG associations in the combined dataset (p = 0.02-0.05). Collectively, these results suggest that protein interactions between LRRTM3, APP and BACE1, as well as complex associations between mRNA levels of LRRTM3, CTNNA3, APP and BACE1 in humans might influence APP metabolism and ultimately risk of AD.
authors.affiliation: Mayo Clinic Florida, Department of Neuroscience, Jacksonville, Florida, USA.
authors.forename: Sarah
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authors.lastname: Lincoln
authors.forename: Mariet
authors.initials: M
authors.lastname: Allen
authors.forename: Claire L
authors.initials: CL
authors.lastname: Cox
authors.forename: Louise P
authors.initials: LP
authors.lastname: Walker
authors.forename: Kimberly
authors.initials: K
authors.lastname: Malphrus
authors.forename: Yushi
authors.initials: Y
authors.lastname: Qiu
authors.forename: Thuy
authors.initials: T
authors.lastname: Nguyen
authors.forename: Christopher
authors.initials: C
authors.lastname: Rowley
authors.forename: Naomi
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authors.lastname: Kouri
authors.forename: Julia
authors.initials: J
authors.lastname: Crook
authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
authors.forename: Samuel
authors.initials: S
authors.lastname: Younkin
authors.forename: Linda
authors.initials: L
authors.lastname: Younkin
authors.forename: Minerva
authors.initials: M
authors.lastname: Carrasquillo
authors.forename: Fanggeng
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authors.lastname: Zou
authors.forename: Samer O
authors.initials: SO
authors.lastname: Abdul-Hay
authors.forename: Wolfdieter
authors.initials: W
authors.lastname: Springer
authors.forename: Sigrid B
authors.initials: SB
authors.lastname: Sando
authors.forename: Jan O
authors.initials: JO
authors.lastname: Aasly
authors.forename: Maria
authors.initials: M
authors.lastname: Barcikowska
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Jada M
authors.initials: JM
authors.lastname: Lewis
authors.forename: Dennis
authors.initials: D
authors.lastname: Dickson
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Eckman
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.forename: Nilüfer
authors.initials: N
authors.lastname: Ertekin-Taner
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding
chemical_list: D016564:Amyloid beta-Protein Precursor; C517878:LRRTM3 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human