A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer%26apos;s disease

作者：Alarcon Marcelo A; Medina Matias A; Hu Qubai; Avila Miguel E; Bustos Bernabe I; Perez Palma Eduardo; Peralta Alexis; Salazar Paulina; Ugarte Giorgia D; Reyes Ariel E; Martin George M; Opazo Carlos; Moon Randall T; De Ferrari Giancarlo V^*

来源：Neurobiology of Aging, 2013, 34(6): 1709.e9.

DOI：10.1016/j.neurobiolaging.2012.11.004

• Alternative splicing
• Alzheimer%26apos
• s disease
• LRP6
• Wnt/beta-catenin signaling

We previously found that single nucleotide polymorphisms in the low-density lipoprotein receptor-related protein 6 (LRP6) gene are associated with Alzheimer%26apos;s disease (AD). Here, we studied the post-transcriptional metabolism of the LRP6 message scanning sequentially the 23 LRP6 exons in human tissues and found a novel LRP6 isoform that completely skips exon 3 (LRP6 Delta 3) in all tissues examined and was also conserved in mice. Expression levels of the LRP6 isoforms were determined in 47 cortical brain messenger (m) RNA samples including 22 AD cases, 11 control subjects, and 14 individuals with other neurological disorders. LRP6 Delta 3 mRNA levels were significantly augmented in AD brains compared with controls (1.6-fold; p = 0.037) or other pathological samples (2-fold; p = 0.007). Functional analysis in Wnt/beta-catenin signaling assays revealed that skipping of exon 3 reduced significantly the signaling activity of the LRP6 coreceptor. We conclude that the LRP6 Delta 3 isoform is a novel splice variant, which shows diminished Wnt/beta-catenin signaling activity and might have a functional role in individuals with AD.

• 出版日期2013-6