miRNA-31 Improves Cognition and Abolishes Amyloid-β Pathology by Targeting APP and BACE1 in an Animal Model of Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by progressive memory impairment, behavioral changes, and, ultimately, loss of consciousness and death. Recently, microRNA (miRNA) dysfunction has been associated with increased production and impaired clearance of amyloid-b (Ab) peptides, whose accumulation is one of the most well-known pathophysiological markers of this disease. In this study, we identified several miRNAs capable of targeting key proteins of the amyloidogenic pathway. The expression of one of these miRNAs, miR-31, previously found to be decreased in AD patients, was able to simultaneously reduce the levels of APP and Bace1 mRNA in the hippocampus of 17-month-old AD triple-transgenic (3xTg-AD) female mice, leading to a significant improvement of memory deficits and a reduction in anxiety and cognitive inflexibility. In addition, lentiviral-mediated miR-31 expression significantly ameliorated AD neuropathology in this model, drastically reducing Ab deposition in both the hippocampus and subiculum. Furthermore, the increase of miR-31 levels was enough to reduce the accumulation of glutamate vesicles in the hippocampus to levels found in non-transgenic age-matched animals. Overall, our results suggest that miR-31-mediated modulation of APP and BACE1 can become a therapeutic option in the treatment of AD.

Social subordination induced by early life adversity rewires inhibitory control of the prefrontal cortex via enhanced Npy1r signaling

“…Detailed methods for behavioral tests, electrophysiology recordings, neuronal labeling with AAV, and confocal imaging, preparation of RNA and DNA samples, RNAseq, methylation assays, qRT-PCR, immunofluorescence, and tissue dissection methodologies were performed as previously described [ 17 – 19 ] and are provided as Supplementary materials and methods .…”

Transcriptomics in Alzheimer’s Disease: Aspects and Challenges

“…MiR-301 reduced the expression of APP and BACE1 in the hippocampus and resulted in an improvement of cognitive functions and reduced anxiety in the mice. This miRNA also lowered the amyloid deposition in the hippocampus and subiculum of mice [125]. Treatment of MiR-132 on primary mouse-human neurons and Tau mutant neurons showed that miR-132 may be protective against amyloid toxicity, and could also reduce the Tau pathology.…”

Reduced Levels of Hsa-mir-342-5p in Plasma Are Associated With Worse Cognitive Evolution in Patients With Mild Alzheimer’s Disease

“…These investigators observed that WT mice treated with miR-30b showed impaired spatial learning and memory retention measured by the Morris water maze and novel object recognition tests [16]. In a study by Borras-Viegas and collaborators, overexpression of miR-31-5p in a 3xTg-AD model resulted in a better performance of animals in the Tmaze, novel object recognition and Barnes maze, which were used for assessing spatial memory and short-term and long-term memory, respectively [32].…”