A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease

Alarcón, Marcelo; Medina, Matías A.; Hu, Qubai; Ávila, Miguel E.; Bustos, Bernabé I.; Pérez‐Palma, Eduardo; Peralta, Alexis; Salazar, Paulina; Ugarte, Giorgia D.; Reyes, Ariel E.; Martin, George M.; Opazo, Carlos; Moon, Randall T.; Ferrari, Giancarlo V. De

doi:10.1016/j.neurobiolaging.2012.11.004

Cited by 47 publications

(28 citation statements)

References 79 publications

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“…Mutations in LRP6 gene have been implicated in late-onset Alzheimer's disease and familial coronary artery disease associated with diabetes and osteoporosis syndrome (46,47). In this study, we extend the mutational spectrum of LRP6 to another complex trait, NTDs, demonstrating a crucial but pleiotropic role of this gene in developmental diseases.…”

Section: Lrp5 and Lrp6: Homologs With A Pleiotropic Role In Human Dismentioning

confidence: 69%

Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway

Allache

Lachance

Guyot

et al. 2013

Human Molecular Genetics

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Wnt signaling has been classified as canonical Wnt/b-catenin-dependent or non-canonical planar cell polarity (PCP) pathway. Misregulation of either pathway is linked mainly to cancer or neural tube defects (NTDs), respectively. Both pathways seem to antagonize each other, and recent studies have implicated a number of molecular switches that activate one pathway while simultaneously inhibiting the other thereby partially mediating this antagonism. The lipoprotein receptor -related protein Lrp6 is crucial for the activation of the Wnt/b-catenin pathway, but its function in Wnt/PCP signaling remains largely unknown. In this study, we investigate the role of Lrp6 as a molecular switch between both Wnt pathways in a novel ENU mouse mutant of Lrp6 (Skax26 m1Jus ) and in human NTDs. We demonstrate that Skax26 m1Jus represents a hypermorphic allele of Lrp6 with increased Wnt canonical and abolished PCP-induced JNK activities. We also show that Lrp6Skax26-Jus genetically interacts with a PCP mutant (Vangl2 Lp ) where double heterozygotes showed an increased frequency of NTDs and defects in cochlear hair cells' polarity. Importantly, our study also demonstrates the association of rare and novel missense mutations in LRP6 that is an inhibitor rather than an activator of the PCP pathway with human NTDs. We show that three LRP6 mutations in NTDs led to a reduced Wnt canonical activity and enhanced PCP signaling. Our data confirm an inhibitory role of Lrp6 in PCP signaling in neurulation and indicate the importance of a tightly regulated and highly dosage-sensitive antagonism between both Wnt pathways in this process.

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Section: Lrp5 and Lrp6: Homologs With A Pleiotropic Role In Human Dismentioning

confidence: 69%

Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway

Allache

Lachance

Guyot

et al. 2013

Human Molecular Genetics

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“…Genome-wide association studies have defined a broad susceptibility region for late-onset AD on chromosome 12, which includes the region encoding LRP6 (De Ferrari et al, 2007). Indeed, two LRP6 SNPs and an alternative splice variant were found to be associated with increased risk of developing AD, which is most likely due to a suppression of Wnt signaling activity (Alarcon et al, 2013; De Ferrari et al, 2007). Despite these implications, the molecular mechanism by which LRP6 regulates AD pathogenesis is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Deficiency in LRP6-Mediated Wnt Signaling Contributes to Synaptic Abnormalities and Amyloid Pathology in Alzheimer’s Disease

Liu

Tsai

Deák

et al. 2014

Neuron

185

192

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SUMMARY Alzheimer’s disease (AD) is an age-related neurological disorder characterized by synaptic loss and dementia. The low-density lipoprotein receptor-related protein 6 (LRP6) is an essential co-receptor for Wnt signaling and its genetic variants have been linked to AD risk. Here we report that neuronal LRP6-mediated Wnt signaling is critical for synaptic function and cognition. Conditional deletion of Lrp6 gene in mouse forebrain neurons leads to age-dependent deficits in synaptic integrity and memory. Neuronal LRP6 deficiency in an amyloid mouse model also leads to exacerbated amyloid pathology due to increased APP processing to amyloid-β. In humans, LRP6 and Wnt signaling are significantly down-regulated in AD brains, likely by a mechanism that depends on amyloid-β. Our results define a critical pathway in which decreased LRP6-mediated Wnt signaling, synaptic dysfunction and elevated Aβ synergistically accelerate AD progression, and suggest that restoring LRP6-mediated Wnt signaling can be explored as a novel strategy for AD therapy.

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“…In addition, the messenger RNA level was significantly increased in AD brains compared with controls (1.6-fold; P = 0.037) and other pathological samples (2-fold; P = 0.007). 61 As shown in these clinical studies, LRP6 is linked to the risk of AD, and plays a pivotal role in AD development and progression.…”

Section: Lrp6 Genetic Polymorphisms and Admentioning

confidence: 91%

Harnessing low-density lipoprotein receptor protein 6 (LRP6) genetic variation and Wnt signaling for innovative diagnostics in complex diseases

et al. 2017

Pharmacogenomics J

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A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease

Cited by 47 publications

References 79 publications

Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway

Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway

Deficiency in LRP6-Mediated Wnt Signaling Contributes to Synaptic Abnormalities and Amyloid Pathology in Alzheimer’s Disease

Harnessing low-density lipoprotein receptor protein 6 (LRP6) genetic variation and Wnt signaling for innovative diagnostics in complex diseases

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