LRRTM3 Interacts with APP and BACE1 and Has Variants Associating with Late-Onset Alzheimer's Disease (LOAD)

Sarah Lincoln, Mariet Allen, Claire L. Cox, Louise P. Walker, Kimberly Malphrus, Yushi Qiu, Thuy Nguyen, Christopher Rowley, Naomi Kouri, Juliana Crook, V. Shane Pankratz, Samuel Younkin, Linda Younkin, Minerva M Carrasquillo, Fanggeng Zou, Samer O. Abdul-Hay, Wolfdieter Springer, Sigrid B. Sando, Jan O. Aasly, Maria BarcikowskaZbigniew K Wszolek, Jada M. Lewis, Dennis W Dickson, Neill R Graff Radford, Ronald Carl Petersen, Elizabeth Eckman, Steven G Younkin, Nilufer Taner

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere64164
JournalPLoS One
Volume8
Issue number6
DOIs
StatePublished - Jun 4 2013

Fingerprint

transmembrane proteins
Alzheimer disease
Leucine
leucine
Alzheimer Disease
Proteins
single nucleotide polymorphism
Polymorphism
Single Nucleotide Polymorphism
leucine-rich repeat proteins
Nucleotides
Adeno-associated virus 3
Messenger RNA
Nested Genes
Genotype
Catenins
Dependovirus
endosomes
genotype
Endosomes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

LRRTM3 Interacts with APP and BACE1 and Has Variants Associating with Late-Onset Alzheimer's Disease (LOAD). / Lincoln, Sarah; Allen, Mariet; Cox, Claire L.; Walker, Louise P.; Malphrus, Kimberly; Qiu, Yushi; Nguyen, Thuy; Rowley, Christopher; Kouri, Naomi; Crook, Juliana; Pankratz, V. Shane; Younkin, Samuel; Younkin, Linda; Carrasquillo, Minerva M; Zou, Fanggeng; Abdul-Hay, Samer O.; Springer, Wolfdieter; Sando, Sigrid B.; Aasly, Jan O.; Barcikowska, Maria; Wszolek, Zbigniew K; Lewis, Jada M.; Dickson, Dennis W; Graff Radford, Neill R; Petersen, Ronald Carl; Eckman, Elizabeth; Younkin, Steven G; Taner, Nilufer.

In: PLoS One, Vol. 8, No. 6, e64164, 04.06.2013.

Research output: Contribution to journalArticle

Lincoln, S, Allen, M, Cox, CL, Walker, LP, Malphrus, K, Qiu, Y, Nguyen, T, Rowley, C, Kouri, N, Crook, J, Pankratz, VS, Younkin, S, Younkin, L, Carrasquillo, MM, Zou, F, Abdul-Hay, SO, Springer, W, Sando, SB, Aasly, JO, Barcikowska, M, Wszolek, ZK, Lewis, JM, Dickson, DW, Graff Radford, NR, Petersen, RC, Eckman, E, Younkin, SG & Taner, N 2013, 'LRRTM3 Interacts with APP and BACE1 and Has Variants Associating with Late-Onset Alzheimer's Disease (LOAD)', PLoS One, vol. 8, no. 6, e64164. https://doi.org/10.1371/journal.pone.0064164
Lincoln, Sarah ; Allen, Mariet ; Cox, Claire L. ; Walker, Louise P. ; Malphrus, Kimberly ; Qiu, Yushi ; Nguyen, Thuy ; Rowley, Christopher ; Kouri, Naomi ; Crook, Juliana ; Pankratz, V. Shane ; Younkin, Samuel ; Younkin, Linda ; Carrasquillo, Minerva M ; Zou, Fanggeng ; Abdul-Hay, Samer O. ; Springer, Wolfdieter ; Sando, Sigrid B. ; Aasly, Jan O. ; Barcikowska, Maria ; Wszolek, Zbigniew K ; Lewis, Jada M. ; Dickson, Dennis W ; Graff Radford, Neill R ; Petersen, Ronald Carl ; Eckman, Elizabeth ; Younkin, Steven G ; Taner, Nilufer. / LRRTM3 Interacts with APP and BACE1 and Has Variants Associating with Late-Onset Alzheimer's Disease (LOAD). In: PLoS One. 2013 ; Vol. 8, No. 6.
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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.",
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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, Juliana

AU - Pankratz, V. Shane

AU - Younkin, Samuel

AU - Younkin, Linda

AU - Carrasquillo, Minerva M

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 W

AU - Graff Radford, Neill R

AU - Petersen, Ronald Carl

AU - Eckman, Elizabeth

AU - Younkin, Steven G

AU - Taner, Nilufer

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.

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