Abstract
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.
Highlights
We have recently shown that miR-132/212 deficiency in 3xTg-Alzheimer’s disease (AD) mice leads to enhanced Tau pathology and memory impairment, which can be rescued in part by the reintroduction of miR-132 mimics[16]
The goal of this study was to determine the impact of miR-132/212 loss on Aβ metabolism
We provide clear in vivo evidence that noncoding RNAs such as miRs are implicated in Aβ production and deposition in mice
Summary
Whether the loss of miR-132/212 participates in the molecular events leading to Aβ deposition is an interesting possibility, and would strengthen a multiple hit scenario for AD6,22. With this in mind, we explored the impact of miR-132/212 loss on Aβ generation and senile plaque deposition in 3xTg-AD mice, a recognized AD mouse model[23]. We explored the impact of miR-132/212 loss on Aβ generation and senile plaque deposition in 3xTg-AD mice, a recognized AD mouse model[23] These experiments showed that miR-132/212 deficiency caused a substantial increase in cerebral Aβ levels as well as amyloid plaque load. Our results add to the literature by providing clear in vivo evidence that the disruption of miR networks can promote Aβ accumulation and deposition, and help define how a single miR can contribute to AD neuropathogenesis and dementia
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