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

ABSTRACT: The abnormal regulation of amyloid-? (A?) 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 A? 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 A? 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 A? production in cells. Finally, both miR-132 and Sirt1 levels correlated with A? 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 A? 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 A? and Tau.

SUBMITTER: Hernandez-Rapp J

PROVIDER: S-EPMC4971468 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Hernandez-Rapp Julia J Rainone Sara S Goupil Claudia C Dorval Véronique V Smith Pascal Y PY Saint-Pierre Martine M Vallée Maxime M Planel Emmanuel E Droit Arnaud A Calon Frédéric F Cicchetti Francesca F Hébert Sébastien S SS

Scientific reports 20160803

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 demons ...[more]

PMID: 27484949

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Project description:It was recently discovered that brain cells release extracellular vesicles (EV) which can pass from brain into blood. These findings raise the possibility that brain-derived EV's present in blood can be used to monitor disease processes occurring in the cerebrum. Since the levels of certain micro-RNAs (miRNAs) have been reported to be altered in Alzheimer's disease (AD) brain, we sought to assess miRNA dysregulation in AD brain tissue and to determine if these changes were reflected in neural EVs isolated from blood of subjects with AD. To this end, we employed high-content miRNA arrays to search for differences in miRNAs in RNA pools from brain tissue of AD (n = 5), high pathological control (HPC) (n = 5), or cognitively intact pathology-free controls (n = 5). Twelve miRNAs were altered by >1.5-fold in AD compared to controls, and six of these were also changed compared to HPCs. Analysis of hits in brain extracts from 11 AD, 7 HPCs and 9 controls revealed a similar fold difference in these six miRNAs, with three showing statistically significant group differences and one with a strong trend toward group differences. Thereafter, we focused on the four miRNAs that showed group differences and measured their content in neurally derived blood EVs isolated from 63 subjects: 16 patients with early stage dementia and a CSF Aβ42+ tau profile consistent with AD, 16 individuals with mild cognitive impairment (MCI) and an AD CSF profile, and 31 cognitively intact controls with normal CSF Aβ42+ tau levels. ROC analysis indicated that measurement of miR-132-3p in neurally-derived plasma EVs showed good sensitivity and specificity to diagnose AD, but did not effectively separate individuals with AD-MCI from controls. Moreover, when we measured the levels of a related miRNA, miR-212, we found that this miRNA was also decreased in neural EVs from AD patients compared to controls. Our results suggest that measurement of miR-132 and miR-212 in neural EVs should be further investigated as a diagnostic aid for AD and as a potential theragnostic.

Dataset Information

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

Publications

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

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