Brains devastated by Alzheimer’s disease (AD) can be “rejuvenated” by restoring the expression of a microRNA molecule, report scientists based at the Leuven Brain Institute and the Netherlands Institute for Neuroscience (NIN). The molecule, miR-132, is one of the most consistently downregulated microRNAs in AD. According to the scientists, miR-132 loss in AD inhibits the generation of new neurons at the hippocampus, where memories are initially formed. The scientists added, however, that miR-132 supplementation can facilitate the generation of new neurons, and thereby alleviate memory deficits in AD.

The new findings appeared in Cell Stem Cell, in an article titled, “Restoring miR-132 expression rescues adult hippocampal neurogenesis and memory deficits in Alzheimer’s disease.” The article begins by pointing out that adult hippocampal neurogenesis (AHN) is functionally linked to mnemonic and cognitive plasticity in humans and rodents. The article then described how AHN inhibition in a mouse model produces memory deficits. Finally, the article reported how “rescuing” AHN—by restoring miR-132—alleviates memory deficits in AD.

“[We] identify miR-132 as a potent regulator of AHN, exerting cell-autonomous proneurogenic effects in adult neural stem cells and their progeny,” the article’s authors wrote. “Using distinct AD mouse models, cultured human primary cells, established neural stem cells, and human patient material, we demonstrate that AHN is directly affected by AD pathology.”

The effects of miR-132 replacement, the authors concluded, corroborate “the significance of AHN in mouse models of AD and reveal the possible therapeutic potential of targeting miR-132 in neurodegeneration.”

The presence of adult-born cells in the hippocampus of old people was recently demonstrated in scientific studies. It suggests that, generally speaking, the so-called process of adult neurogenesis is sustained throughout adulthood. Adult neurogenesis is linked to several aspects of cognition and memory in both animal models and humans, and it was reported to sharply decrease in the brains of patients with Alzheimer’s disease.

Researchers also found that higher levels of adult neurogenesis in these patients seem to correlate with better cognitive performance before death. “This could suggest that the adult-born neurons in our brain may contribute to a sort of cognitive reserve that could later on provide higher resilience to memory loss,” said Evgenia Salta, PhD, group leader at the NIN and a corresponding author of the new study.

“Seven years ago, while studying a small RNA molecule that is expressed in our brain, called miR-132, we came across a rather unexpected observation,” Salta continued. “This molecule, which we had previously found to be decreased in the brain of AD patients, seemed to regulate homeostasis of neural stem cells in the central nervous system.”

Back then, AD was thought to be a disease affecting only mature neuronal cells, so at first glance this finding did not seem to explain a possible role of miR-132 in the progression of AD. In this study, the researchers set out to address whether miR-132 can regulate adult hippocampal neurogenesis in healthy and Alzheimer’s brains. Using distinct AD mouse models, cultured human neural stem cells, and postmortem human brain tissue, the researchers discovered that miR-132 is required for the neurogenic process in the adult hippocampus.

Graphical abstract for “Restoring miR-132 expression rescues adult hippocampal neurogenesis and memory deficits in Alzheimer’s disease.” [Cell Stem Cell]

“Decreasing the levels of miR-132 in the adult mouse brain or in human neural stem cells in a dish impairs the generation of new neurons. However, restoring the levels of miR-132 in AD mice rescues neurogenic deficits and counteracts memory impairment related to adult neurogenesis,” explained Sarah Snoeck, a technician in Salta’s group and a co-author of the current study.

These results provide a proof-of-concept regarding the putative therapeutic potential of bringing about adult neurogenesis in Alzheimer’s. “Our next goal,” Salta declared, “is to systematically assess the efficacy and safety of targeting miR-132 as a therapeutic strategy in AD.”

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