Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease

Abstract

Genome-wide linkage studies have defined a broad susceptibility region for late-onset Alzheimer's disease on chromosome 12, which contains the Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) gene, a coreceptor for Wnt signaling. Here, we report the association between common LRP6 variants and late-onset Alzheimer's disease in a multicenter case-control series as well as in a large family-based series ascertained by the National Institute of Mental Health-National Institute on Aging Genetics Initiative. As shown in the genome-wide linkage studies, our association depends mainly on apolipoprotein E-4 (APOE-4) carrier status. Haplotype tagging single-nucleotide polymorphisms (SNPs) with a set of seven allelic variants of LRP6 identified a putative risk haplotype, which includes a highly conserved coding sequence SNP: Ile-1062 3 Val. Functional analyses revealed that the associated allele Val-1062, an allele previously linked to low bone mass, has decreased ␤-catenin signaling in HEK293T cells. Our study unveils a genetic relationship between LRP6 and APOE and supports the hypothesis that altered Wnt/␤-catenin signaling may be involved in this neurodegenerative disease.neurodegenerative ͉ LRP-6 ͉ single-nucleotide polymorphism ͉ APOE ͉ Wnt

The effects of aging on the expression of Wnt pathway genes in mouse tissues

“…This pathway has recently also emerged as potentially a key regulator of cellular senescence (Ye et al 2007). Consistent with these anti-aging properties, several reports have documented that inherited genetic polymorphisms that result in reduced Wnt signaling are associated with premature aging phenotypes such as heart disease, metabolic syndrome, Alzheimer's disease, osteoporosis, and diabetes (De Ferrari et al 2007;Gong et al 2001;Mani et al 2007;Soriano et al 2001;Welters and Kulkarni 2008). This genetic evidence is consistent with the idea that maintenance of Wnt signaling is required for stem cell homeostasis and hence acts to delay aging processes.…”

RoR2 functions as a noncanonical Wnt receptor that regulates NMDAR-mediated synaptic transmission

“…Because of the importance of NMDARs in synaptic function (14,15), regulation of NMDARs by RoR2 signaling provides a mechanism for Wnt ligands to modulate basal synaptic transmission, synaptic plasticity, and brain functions acutely beyond embryonic development. Several neuropathologies in adulthood in which dysfunction of NMDARs have been implicated have also been associated with dysregulation of Wnt signaling pathways, including schizophrenia (7,8), bipolar disorder (28), and Alzheimer's disease (5,6), suggesting that Wnt signaling cascades might also play a part in synaptic maintenance and function. The requirement of RoR2 signaling to maintain proper levels of NMDAR-mediated synaptic transmission provides a mechanism to better understand some of these neuropathologies in which glutamatergic synaptic transmission has been compromised.…”

“…They play a key role in morphogenesis, patterning, and lineage decision during central and peripheral nervous system development (3). Wnt ligands control gene expression (4), and their dysregulation has been implicated in cancer and major neuropathologies (5)(6)(7)(8)(9).…”

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…1). LRP1 has been repeatedly, albeit weakly, associated with AD risk (Beffert et al 1999;Vazquez-Higuera et al 2009), and a coding polymorphism in the distantly related Wnt coreceptor LRP6 has also been implicated (De Ferrari et al 2007). None of the other family members have so far been convincingly associated with AD by human genetic data.…”