Alzheimer's disease: New study reveals small molecules can significantly affect many brain cells

A recent study from the Netherlands Institute for Neuroscience and the VIB-KU Leuven Centre for Brain and Disease Research demonstrates that a little molecule known as microRNA-132 can significantly affect many brain cells and may be related to Alzheimer's disease.

Like DNA, RNA is a molecule made up of a number of connected building pieces. It has long been believed that RNA solely acts as a messenger and copy of DNA, allowing DNA to be translated into proteins. There are, however, some RNA fragments that do not code for proteins. One of these non-coding RNA molecules is the microRNA. Despite their diminutive size, they can perform important tasks because they may bind to RNA and affect how genes and proteins are expressed. MicroRNAs are frequently dysregulated in a wide range of disorders, including Alzheimer's.

MicroRNA profiles are frequently disrupted and altered in Alzheimer's patients, with microRNA-132 levels falling noticeably in particular. But does this chemical actually contribute to the illness, or may this decline just be a coincidence? Increased levels of microRNA-132, according to prior studies using mouse models, led to the creation of new brain cells and better memory in the mice. While many scientists think that the protein amyloid is the main contributor to Alzheimer's disease, other factors including inflammation and the protein tau also seem to be significant. In mice, microRNA-132 has a beneficial impact on the amyloid and tau diseases. But the precise mechanics are still a mystery.

Researchers Hannah Walgrave, Amber Penning, Sarah Snoeck, Giorgia Tosoni, and their team, led by Evgenia Salta (in collaboration with the group of Bart De strooper at KU Leuven-VIB, Belgium) investigated the effects of microRNA-132 in different cell types. They manipulated the levels of microRNA-132 in a mouse model by both increasing and decreasing them. Subsequently, they used a special technique called single-cell RNA sequencing to examine the genes that changed in each cell type in the brain.

Amber Penning: "A microRNA can have numerous targets, which makes them interesting for diseases with multiple pathological aspects. However, this also makes them challenging to study because how do you find those targets? We know that microRNA-132 performs various functions in neurons, but surprisingly, we found that this microRNA also plays a role in microglia, the immune cells of the brain. This is interesting in the case of Alzheimer's because we believe that neuroinflammation plays a significant role."

"When we increase microRNA-132 in these microglia, we observe a shift from a disease-associated state to a more balanced homeostatic state. We see this result in both mouse brain and human cell lines. However, whether this change is positive or negative requires further investigation through follow-up experiments. There are different theories suggesting that this disease-associated state may initially aid in cell clearance during the early stages of the disease but becomes excessive later, leading to the death of healthy cells. We still need to determine how beneficial it is for the cells to become more homeostatic. Therefore, we need to be cautious in drawing conclusions."

"The most significant aspect of this study is demonstrating that microRNA-132 also plays a role in microglia and can influence neuroinflammation. The next step is to examine whether increasing microRNA-132 in neurons and microglia in an Alzheimer's mouse model has any actual effect. The same applies to the human cell lines we used. In this research, we only used a healthy control cell line, but we will conduct further tests in Alzheimer's cell lines to see if there are any effects."

“The ultimate goal would be to increase microRNA-132 in Alzheimer's patients as a therapeutic strategy. Currently, we are using viruses (containing the microRNA) in Alzheimer's mice that can be injected intravenously, directly into the veins. This makes it easier to eventually translate this strategy to the clinic, as we are utilizing a virus that, in theory, can also be injected into an arm. In addition to Alzheimer's, there are other neurodegenerative diseases that exhibit a decrease in the same microRNA. Therefore, these results may also be relevant to other disease conditions.”

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