microRNA-132/212 deficiency enhances Aβ production and senile plaque deposition in Alzheimer's disease triple transgenic mice.

Autor:	Hernandez-Rapp J; Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.; Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada., Rainone S; Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.; Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada., Goupil C; Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.; Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada., Dorval V; Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.; Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada., Smith PY; Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.; Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada., Saint-Pierre M; Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.; Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada., Vallée M; Axe Endocrinologie et néphrologie, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada., Planel E; Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.; Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada., Droit A; Axe Endocrinologie et néphrologie, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.; Département de médecine moléculaire, Université Laval, Québec, QC, G1V 0A6, Canada., Calon F; Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.; Faculté de pharmacie, Université Laval, Québec, QC, G1V 0A6, Canada., Cicchetti F; Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.; Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada., Hébert SS; Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, G1V4G2, Canada.; Département de psychiatrie et neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2016 Aug 03; Vol. 6, pp. 30953. Date of Electronic Publication: 2016 Aug 03.
DOI:	10.1038/srep30953
Abstrakt:	The abnormal regulation of amyloid-β (Aβ) metabolism (e.g., production, cleavage, clearance) plays a central role in Alzheimer's disease (AD). Among endogenous factors believed to participate in AD progression are the small regulatory non-coding microRNAs (miRs). In particular, the miR-132/212 cluster is severely reduced in the AD brain. In previous studies we have shown that miR-132/212 deficiency in mice leads to impaired memory and enhanced Tau pathology as seen in AD patients. Here we demonstrate that the genetic deletion of miR-132/212 promotes Aβ production and amyloid (senile) plaque formation in triple transgenic AD (3xTg-AD) mice. Using RNA-Seq and bioinformatics, we identified genes of the miR-132/212 network with documented roles in the regulation of Aβ metabolism, including Tau, Mapk, and Sirt1. Consistent with these findings, we show that the modulation of miR-132, or its target Sirt1, can directly regulate Aβ production in cells. Finally, both miR-132 and Sirt1 levels correlated with Aβ load in humans. Overall, our results support the hypothesis that the miR-132/212 network, including Sirt1 and likely other target genes, contributes to abnormal Aβ metabolism and senile plaque deposition in AD. This study strengthens the importance of miR-dependent networks in neurodegenerative disorders, and opens the door to multifactorial drug targets of AD by targeting Aβ and Tau.
Databáze:	MEDLINE
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