Tiny they may be, but don’t let their size fool you. At only 21-23 nucleotides in length, microRNAs orchestrate grand biological processes, and researchers are just starting to get a sense of their complex roles in neurodegenerative disease. At the 13th International Conference on Alzheimer’s and Parkinson’s Diseases, held March 29-April 2 in Vienna, researchers presented new data on miR-132, a microRNA produced in the brain that wanes as AD sets in. miR-132, it turns out, stymies accumulation of Aβ and tau accumulation in young mice though, curiously, in older mice it appears to boost the birth of new neurons. Other researchers reported that this microRNA drops in people with vascular dementia as well. The findings cast microRNAs as dynamic genetic modulators that wear different hats throughout the aging and disease processes.
The emerging data should caution researchers against drawing simple conclusions about these small nucleic acid snippets, commented Sébastien Hébert of the University of Laval in Montreal.
Neuronal Nursery. With their cell bodies huddled in the subgranular layer (SGL) of the hippocampus, neural stem cells expressing Nestin and GFAP are the source of newborn neurons (GCL: granular cell layer, MCL: molecular cell layer). [Image courtesy of Evgenia Salta.]
Transcribed from the genomic backwaters of introns and intergenic regions, microRNAs block the translation of their mRNA targets, either by obstructing translation machinery or by recruiting gene-silencing equipment. The expression of microRNAs changes throughout development and aging, and researchers have also reported the under- or overexpression of particular microRNAs in the brains of people with neurodegenerative disease. MiR-132 expression is consistently downregulated in postmortem brain samples of people with AD (see Research Timeline 2010; Hébert et al., 2013; Pichler et al., 2017; and reviewed in Salta and De Strooper, 2017).
Two recent papers published in close succession—one led by Hébert, the other by his former mentor, Bart De Strooper at KU Leuven in Belgium—reported that deleting or downregulating miR-132 in young AD mice worsened Aβ and tau pathology, while (in De Strooper’s study) overexpressing miR-132 diminished pathology (see Hernandez-Rapp et al., 2016; Salta et al., 2016).
At AD/PD, Evgenia Salta, a postdoc in De Strooper’s lab, updated the crowd on a plot twist to this story. It came about when the researchers tested whether overexpressing miR-132 would slow cognitive decline in older, plaque-ridden mice. Indeed, Salta reported that 9-month-old APPPS1 mice given intracerebroventricular injections of miR-132 outperformed mice given a control microRNA on memory tests. Because this microRNA had vanquished Aβ and tau pathology in younger animals, Salta hypothesized that this is what would explain the cognitive benefit in the older ones. Not so. The researchers found no significant differences in Aβ pathology or phosphorylated tau in response to miR-132 overexpression, Salta reported. Hébert told Alzforum that, similar to what Salta observed in 9-month-old APPPS1 mice, he also found no consistent effect of miR-132 on Aβ and tau pathology in older 3xTg animals.
If not by lightening the pathology burden, then how might miR-132 boost memory in older AD mice? In search of hints, the researchers turned back to a previous paper, in which they had identified miR-132’s mRNA targets in the central nervous system of zebrafish (see Salta et al., 2014). In a nutshell, the researchers previously reported that miR-132 promotes the differentiation of new neurons from neural stem cells in the dentate gyrus, called radial glial progenitor cells. Given that neurogenesis takes a nosedive in multiple AD mouse models with age, might enhanced neurogenesis explain the memory boost in the 9-month-old APPPS1 animals treated with miR-132?
To test this, Salta and colleagues gave the animals running wheels. This exercise is a known neurogenesis booster. After a month, the researchers checked the radial glial progenitor cells for recent proliferation, the first step in neurogenesis. Among wild-type mice, both young and old had proliferating stem cells in response to running, but in APPPS1 mice, only youngsters did. Salta pointed out that both wild-type and AD mice ran similar distances, as measured by monitors fitted to the running wheels. Injection of miR-132 rescued this neurogenesis defect in the older AD mice. Conversely, knocking down miR-132 in old wild-type animals decreased proliferation, Salta reported.
Could boosting miR-132 expression slow cognitive decline in people with Alzheimer’s? Salta said existing data leave it unclear whether waning neurogenesis plays a role in cognitive decline in AD. She believes that even if flagging neurogenesis does not contribute to cognitive decline in AD, boosting it could still be beneficial. New neurons are fitter, more plastic, and better at absorbing new information than their older counterparts, she said. Salta and colleagues are working to confirm their preliminary findings, and to understand how miR-132 might drive neurogenesis.
Thickening the microRNA plot and expanding it into humans, at AD/PD Jose Gerardo-Aviles, a graduate student in Patrick Kehoe’s lab at the University of Bristol, U.K., described expression of seven microRNAs in the posterior cingulate gyrus of postmortem samples from people with AD, vascular dementia, or healthy controls. Gerardo-Aviles reported that the tissue concentration of four microRNAs—miR-16, miR-29a, miR-34a, and miR-125b—increased with higher Braak stage in AD patients, but not in people with vascular dementia, compared to controls. Together, these microRNAs reduced the expression of retinoic acid receptor-related orphan receptor-alpha (RORα), itself a transcriptional regulator involved in lipid metabolism, hypoxia, and the circadian clock.
An opposing pattern emerged for miR-132 and miR-212, both of which were downregulated in people with AD as the disease progressed, and in those with vascular dementia, Gerardo-Aviles reported. He proposed that the link to vascular dementia could be explained by the importance of pericyte-derived miR-132 in stimulating angiogenesis in response to hypoxia. “As highlighted by Salta’s talk, restoring miR-132 levels might represent a multi-hit therapeutic strategy in AD, and we consider this might be also helpful to vascular dementia,” he told Alzforum.
Hébert struck a more cautious tone. The changing role of miR-132 with age in his and Salta’s mice illustrates a key issue in the microRNA field, he said. Just as microRNA expression changes with age and in different disease states, so does the expression of their mRNA targets. Target expression differs between cell types, and neuroinflammatory or vascular problems might change target expression and render microRNA pathways less effective, he proposed. These fluid changes make it unlikely that a single microRNA will work as a therapeutic magic bullet, Hébert said. —Jessica Shugart
Research Models Citations
- Hébert SS, Wang WX, Zhu Q, Nelson PT. A Study of Small RNAs from Cerebral Neocortex of Pathology-Verified Alzheimer's Disease, Dementia with Lewy Bodies, Hippocampal Sclerosis, Frontotemporal Lobar Dementia, and Non-Demented Human Controls. J Alzheimers Dis. 2013 Jan 1;35(2):335-48. PubMed.
- Pichler S, Gu W, Hartl D, Gasparoni G, Leidinger P, Keller A, Meese E, Mayhaus M, Hampel H, Riemenschneider M. The miRNome of Alzheimer's disease: consistent downregulation of the miR-132/212 cluster. Neurobiol Aging. 2017 Feb;50:167.e1-167.e10. Epub 2016 Oct 3 PubMed.
- Salta E, De Strooper B. microRNA-132: a key noncoding RNA operating in the cellular phase of Alzheimer's disease. FASEB J. 2017 Feb;31(2):424-433. PubMed.
- Hernandez-Rapp J, Rainone S, Goupil C, Dorval V, Smith PY, Saint-Pierre M, Vallée M, Planel E, Droit A, Calon F, Cicchetti F, Hébert SS. microRNA-132/212 deficiency enhances Aβ production and senile plaque deposition in Alzheimer's disease triple transgenic mice. Sci Rep. 2016 Aug 3;6:30953. PubMed.
- Salta E, Sierksma A, Vanden Eynden E, De Strooper B. miR-132 loss de-represses ITPKB and aggravates amyloid and TAU pathology in Alzheimer's brain. EMBO Mol Med. 2016 Sep 1;8(9):1005-18. PubMed.
- Salta E, Lau P, Sala Frigerio C, Coolen M, Bally-Cuif L, De Strooper B. A self-organizing miR-132/Ctbp2 circuit regulates bimodal notch signals and glial progenitor fate choice during spinal cord maturation. Dev Cell. 2014 Aug 25;30(4):423-36. Epub 2014 Aug 14 PubMed.