A recent study conducted by the Netherlands Institute for Neuroscience and the VIB-KU Leuven Center for Brain and Disease Research has shed light on the potential impact of a tiny molecule known as microRNA-132 on various brain cells, suggesting its involvement in Alzheimer’s disease.
RNA, similar to DNA, is composed of interconnected units and has traditionally been viewed as a messenger and copy of DNA, facilitating the translation of DNA into proteins. However, certain types of RNA, such as microRNAs, do not encode for proteins and are categorized as non-coding RNA molecules.
Despite their small size, microRNAs can exert significant influence by binding to RNA molecules, thereby affecting gene and protein expression. Dysregulation of microRNAs is frequently observed in various diseases, including Alzheimer’s disease.
Individuals with Alzheimer’s often display disrupted and altered microRNA profiles, particularly a notable decrease in microRNA-132. Nonetheless, it remains unclear whether this molecule truly contributes to the disease or if its reduced levels are merely coincidental. Previous studies conducted on mouse models have demonstrated that augmenting microRNA-132 levels led to the generation of new brain cells and improved memory in mice.
While many researchers believe that the protein amyloid primarily instigates Alzheimer’s disease, another protein called tau and inflammation also appear to play significant roles. In mice, microRNA-132 has exhibited positive effects on both amyloid and tau pathologies. However, the precise mechanisms by which these effects are achieved remain unknown.
Effect of microRNA-132 in different cell types
A team of researchers, including Hannah Walgrave, Amber Penning, Sarah Snoeck, Giorgia Tosoni, and led by Evgenia Salta in collaboration with the group of Bart De Strooper at KU Leuven-VIB, Belgium, conducted a study delving into the impact of microRNA-132 across different cell types. To investigate its effects, they manipulated the levels of microRNA-132 in a mouse model, both increasing and decreasing them. They then employed a specialized technique called single-cell RNA sequencing to analyze the gene alterations in each specific cell type within the brain.
Amber Penning elaborated on the study, stating, “MicroRNAs have the potential to target numerous molecules, making them intriguing for diseases with multiple pathological aspects. However, this also presents a challenge in studying them, as identifying their targets becomes complex. While we were aware of the various functions of microRNA-132 in neurons, we made an intriguing discovery that it also plays a role in microglia, the immune cells of the brain. This finding holds significance for Alzheimer’s disease, as we believe that neuroinflammation plays a pivotal role.”
Changes in cell state
Upon increasing microRNA-132 levels in microglia, a notable shift from a disease-associated state to a more balanced homeostatic state was observed in both mouse brain and human cell lines. However, further investigations and follow-up experiments are necessary to ascertain whether this change has positive or negative implications.
Various theories propose that the disease-associated state initially aids in cellular clearance during the early stages of Alzheimer’s disease but becomes excessive later, leading to the demise of healthy cells. Determining the extent of benefits derived from achieving a more homeostatic state requires careful scrutiny, and thus, caution must be exercised in drawing conclusions.
The study’s paramount finding lies in the revelation that microRNA-132 also influences microglia and exerts an impact on neuroinflammation. The subsequent step entails examining the potential effects of augmenting microRNA-132 levels in neurons and microglia within an Alzheimer’s mouse model. Similarly, investigations using Alzheimer’s cell lines will be conducted to discern any effects, as the research thus far has solely utilized a healthy control cell line.
Ultimate goal
The ultimate objective is to develop a therapeutic approach that involves increasing microRNA-132 levels in Alzheimer’s patients. Currently, the researchers are utilizing viruses containing the microRNA in Alzheimer’s mice, which can be administered intravenously, facilitating potential translation of this strategy to clinical applications. The advantage lies in using a virus that can theoretically be injected into a patient’s arm, simplifying the process.
It is worth noting that apart from Alzheimer’s disease, other neurodegenerative disorders also exhibit a decrease in the same microRNA. Therefore, the findings from this study may hold relevance to a broader spectrum of disease conditions.
The study documenting these findings has been published in the scientific journal iScience.