TY - JOUR
T1 - LRRTM3 Interacts with APP and BACE1 and Has Variants Associating with Late-Onset Alzheimer's Disease (LOAD)
AU - Lincoln, Sarah
AU - Allen, Mariet
AU - Cox, Claire L.
AU - Walker, Louise P.
AU - Malphrus, Kimberly
AU - Qiu, Yushi
AU - Nguyen, Thuy
AU - Rowley, Christopher
AU - Kouri, Naomi
AU - Crook, Julia
AU - Pankratz, V. Shane
AU - Younkin, Samuel
AU - Younkin, Linda
AU - Carrasquillo, Minerva
AU - Zou, Fanggeng
AU - Abdul-Hay, Samer O.
AU - Springer, Wolfdieter
AU - Sando, Sigrid B.
AU - Aasly, Jan O.
AU - Barcikowska, Maria
AU - Wszolek, Zbigniew K.
AU - Lewis, Jada M.
AU - Dickson, Dennis
AU - Graff-Radford, Neill R.
AU - Petersen, Ronald C.
AU - Eckman, Elizabeth
AU - Younkin, Steven G.
AU - Ertekin-Taner, Nilüfer
N1 - Funding Information:
We have the following interests: N. Graff-Radford has served as a consultant to Codman and received grant support from Elan Pharmaceutical Research, Pfizer Pharmaceuticals, Medivation, and Forrest. R.C. Petersen has been a consultant to GE Healthcare and Elan Pharmaceuticals, has served on a data safety monitoring board in clinical trials sponsored by Pfizer Incorporated and Janssen Alzheimer Immunotherapy, and gave a CME lecture at Novartis Incorporated. The mouse strain used for this research project, B6;129S5-Lrrtm3tm1Lex/Mmcd, identification number 032451-UCD was donated to the Mutant Mouse Regional Resource Center MMRRC by Genentech, Inc. MMRC is a NCRR-NIH-funded strain repository. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
PY - 2013/6/4
Y1 - 2013/6/4
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0064164
DO - 10.1371/journal.pone.0064164
M3 - Article
C2 - 23750206
AN - SCOPUS:84878643581
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 6
M1 - e64164
ER -