Effect of Genetic Variation in LRRTM3 on Risk of Alzheimer Disease

Reitz, Christiane; Conrad, Christopher; Roszkowski, Katherine; Rogers, Robert S.; Mayeux, Richard

doi:10.1001/archneurol.2011.2463

Cited by 17 publications

(13 citation statements)

References 32 publications

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“…Four SNPs belonging to two distinct LD blocks and including one promoter SNP were associated (rs16923760, rs1925608, rs7082306, rs1925609) as were their corresponding haplotypes. In functional analyses LRRTM3 knockdown with small-hairpin RNAs caused a significant decrease in amyloid precursor protein processing compared with the scrambled small-hairpin RNA condition consistent with the notion that that LRRTM3 may modulate γ-secretase processing of APP(83). …”

Section: Genetic Studies In Caribbean Hispanics Outside the Apoe Regionsupporting

confidence: 77%

“…The authors identified three SNPs (rs17219084, rs11075996, rs11075997) that were associated with LOAD, consistent with independent studies in non-Hispanic Whites showing that polymorphisms in the FTO gene have robust effects on obesity, obesity-related traits and endophenotypes associated with LOAD(79–82). In the same cohort, the authors explored the association between SNPs in leucine-rich repeat transmembrane 3 ( LRRTM3 ) gene and LOAD (83). LRRTM3 is a neuronal gene-promoting amyloid precursor protein (APP) processing by β-secretase 1 thereby modulating the levels of Aβ40 and Aβ42.…”

Section: Genetic Studies In Caribbean Hispanics Outside the Apoe Regionmentioning

confidence: 99%

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Genetics of Alzheimer’s Disease in Caribbean Hispanic and African American Populations

Reitz

Mayeux

2014

Biological Psychiatry

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Late-onset Alzheimer’s disease, which is characterized by progressive deterioration in cognition, function and behavior, is the most common cause of dementia and the sixth leading cause of all deaths placing a considerable burden on western societies. Most studies aiming to identify genetic susceptibility factors for LOAD have focused on non-Hispanic white populations. This is, in part related to differences in linkage disequilibrium and allele frequencies between ethnic groups that could lead to confounding. However, in addition, non-Hispanic white populations are simply more widely studied. As a consequence, minorities are genetically under-represented despite the fact that in several minority populations living in the same community as Whites (including African American and Caribbean Hispanics) LOAD incidence is higher. This review summarizes the current knowledge on genetic risk factors associated with LOAD risk in Caribbean Hispanics and African Americans and provides suggestions for future research. We focus on Caribbean Hispanics and African Americans as they have a high LOAD incidence and a body of genetic studies on LOAD that is based on samples with GWAS data and reasonable large effect sizes to yield generalizable results.

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Section: Genetic Studies In Caribbean Hispanics Outside the Apoe Regionsupporting

confidence: 77%

Section: Genetic Studies In Caribbean Hispanics Outside the Apoe Regionmentioning

confidence: 99%

Genetics of Alzheimer’s Disease in Caribbean Hispanic and African American Populations

Reitz

Mayeux

2014

Biological Psychiatry

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“…[2,4] Moreover, experimental studies of the role of membrane in protein aggregation have demonstrated sensitive dependence of protein-membrane interaction on the abundance of CHOL, [11,12] and CHOL is suspected to play a crucial role in the genesis of some cardio vascular disorders, lung diseases, and diseases that affect brain functions like Parkinson's and Alzheimer's diseases. [13,14] In recent atomistic simulations of CHOL-containing DMPC lipid bilayers, CHOL monomer orientations were observed to be strongly correlated with sterol composition. [15] Binary lipid mixtures of CHOL and DMPC in 1:1 and 1:2 ratios have been studied and CHOL aggregation observed for elevated CHOL concentration.…”

Section: Introductionmentioning

confidence: 99%

Exploring the structure and stability of cholesterol dimer formation in multicomponent lipid bilayers

et al. 2016

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For forty years, the existence and possible functional importance of cholesterol dimer formation has been discussed. Due to challenges associated with structural studies of membrane lipids, there has as yet been no direct experimental verification of the existence and relevance of the cholesterol dimer. Building on recent advances in lipid force fields for molecular simulation, in this work the structure and stability of the cholesterol dimer is characterized in POPC bilayers in absence and presence of sphingomyelin. The cholesterol dimer structural ensemble is found to consist of sub-states that reflect, but also differ from, previously proposed dimer structures. While face-to-face dimer structures predominate, no evidence is found for the existence of tail-to-tail dimers in POPC lipid bilayers. Near stoichiometric complex formation of cholesterol with sphingomyelin is found to effect cholesterol dimer structure without impacting population. Comparison with NMR-derived order parameters provide validation for the simulation model employed and conclusions drawn related to the structure and stability of cholesterol dimers in multicomponent lipid bilayers.

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“…However, changes in LRRTM3 expression have no signifi cant effect on BACE1 activity, nor do LRRTM3 and APP demonstrate a high degree of co-localization (Majercak et al 2006 ). Another study performed with several different shRNA constructs revealed that knockdown of LRRTM3 results in a reduced processing of APP (Reitz et al 2012 ). Recently, the effect of LRRTM3 on APP processing was investigated in in vivo studies employing Lrrtm3 -knockout mice and AβPPswe/PS1dE9 transgenic mice (mice containing the "Swedish" double point mutations in APP along with a mutation causing mis-splicing of exon 9 of mRNA encoding presenilin 1; all mutations associated with early-onset familial forms of AD).…”

Section: Diseasesmentioning

confidence: 99%

“…A large region of chromosome 10, including the region encoding LRRTM3, has received attention in relation to the development of late-onset AD. Investigations of SNPs potentially related to late-onset AD, as well as other statistical and genetic studies, have observed SNPs in LRRTM3 as well as CCTNNA3 (the α-Catenin-encoding gene in which LRRTM3 is nested in an intron) and identifi ed LRRTM3 as a potential late-onset AD candidate gene (Reitz et al 2012 ;Liang et al 2007 ;Thornton-Wells et al 2008 ;Edwards et al 2009 ).…”

Section: Diseasesmentioning

confidence: 99%

Neural Cell Adhesion Molecules Belonging to the Family of Leucine-Rich Repeat Proteins

Winther

Walmod

2013

Advances in Neurobiology

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Leucine-rich repeats (LRRs) are motifs that form protein-ligand interaction domains. There are approximately 140 human genes encoding proteins with extracellular LRRs. These encode cell adhesion molecules (CAMs), proteoglycans, G-protein-coupled receptors, and other types of receptors. Here we give a brief description of 36 proteins with extracellular LRRs that all can be characterized as CAMs or putative CAMs expressed in the nervous system. The proteins are involved in multiple biological processes in the nervous system including the proliferation and survival of cells, neuritogenesis, axon guidance, fasciculation, myelination, and the formation and maintenance of synapses. Moreover, the proteins are functionally implicated in multiple diseases including cancer, hearing impairment, glaucoma, Alzheimer's disease, multiple sclerosis, Parkinson's disease, autism spectrum disorders, schizophrenia, and obsessive-compulsive disorders. Thus, LRR-containing CAMs constitute a large group of proteins of pivotal importance for the development, maintenance, and regeneration of the nervous system.

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Effect of Genetic Variation in LRRTM3 on Risk of Alzheimer Disease

Cited by 17 publications

References 32 publications

Genetics of Alzheimer’s Disease in Caribbean Hispanic and African American Populations

Genetics of Alzheimer’s Disease in Caribbean Hispanic and African American Populations

Exploring the structure and stability of cholesterol dimer formation in multicomponent lipid bilayers

Neural Cell Adhesion Molecules Belonging to the Family of Leucine-Rich Repeat Proteins

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