Summary: Researchers have discovered that a small molecule, microRNA-132, may play an important role in Alzheimer’s disease.
In Alzheimer’s patients, microRNA-132 levels are often disrupted and significantly reduced. Although microRNA-132 was known to have various functions in neurons, this study surprisingly revealed its role in microglia, the brain’s immune cells.
The researchers believe this discovery could open a new path in the understanding and potential treatment of Alzheimer’s disease and other neurodegenerative disorders.
Key facts:
- MicroRNAs, such as microRNA-132, are non-coding RNA molecules, meaning they do not code for proteins. However, they can bind to RNA and affect the expression of genes and proteins, playing a critical role in various biological processes and diseases.
- Studies in mouse models have previously shown that increasing levels of microRNA-132 leads to the generation of new brain cells and improved memory, highlighting its potential therapeutic value in neurodegenerative diseases such as Alzheimer’s.
- Alzheimer’s disease has traditionally been associated with abnormal amounts of two proteins: amyloid beta and tau. However, this study suggests that noncoding RNA molecules such as microRNA-132, which affect both neurons and microglia, may also be key players in disease progression.
source: KNOW
A new study by Netherlands Institute of Neurology and on VIB-KU Leuven Center for Brain and Disease Research shows that a very small molecule called microRNA-132 can have significant effects on various brain cells and may play a role in Alzheimer’s disease.
RNA is a molecule that, like DNA, consists of a series of linked building blocks. For a long time, it was thought that RNA served only as a messenger and a copy of DNA, enabling the translation of DNA into proteins. However, there are also parts of RNA that do not code for proteins.
MicroRNAs are an example of these non-coding RNA molecules. Although they are small in size, they can have an essential function: they can bind to RNA and thus influence the expression of genes and proteins. In many different diseases, including Alzheimer’s, microRNAs are often dysregulated.
Alzheimer’s patients often exhibit disrupted and altered microRNA profiles, particularly a significant decrease in microRNA-132. Credit: Neuroscience NewsAlzheimer’s patients often exhibit disrupted and altered microRNA profiles, particularly a significant decrease in microRNA-132. But does this molecule really play a role in the disease, or is this reduction just a coincidence?
Previous studies in mouse models have shown that increasing levels of microRNA-132 leads to the generation of new brain cells and improved memory in mice. Although many researchers believe that the protein amyloid is the main cause of Alzheimer’s disease, another protein called tau and inflammation also appear to play an important role.
MicroRNA-132 shows a positive effect on amyloid and tau pathologies in mice. However, the exact mechanisms are still unknown.
Effect of microRNA-132 in different cell types
Researchers Hannah Walgrave, Amber Penning, Sarah Snoeck, Giorgia Tosoni and their team led by Evgenia Salta (in collaboration with Bart De strooper’s group at KU Leuven-VIB, Belgium) are investigating the effects of microRNA-132 in different cell types.
They manipulated microRNA-132 levels in a mouse model by increasing and decreasing them. They then used a special technique called single-cell RNA sequencing to examine the genes that change in each type of cell in the brain.
Amber Penning: “MicroRNAs can have multiple targets, which makes them interesting for diseases with multiple pathological aspects. However, this also makes them challenging to study because how do you find these targets?
We know that microRNA-132 performs a variety of functions in neurons, but we surprisingly found that this microRNA also plays a role in microglia, the brain’s immune cells. This is interesting in the case of Alzheimer’s disease because we believe that neuroinflammation plays an important role.
Changes in the state of the cell
“When we increase microRNA-132 in these microglia, we observe a shift from a disease-related 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 various theories that suggest that this disease-related condition may initially help clear cells during the early stages of the disease, but becomes excessive later, leading to the death of healthy cells.” We have yet to determine how beneficial it is for cells to become more homeostatic. So we have to be cautious in our conclusions.”
“The most important aspect of this study is the demonstration that microRNA-132 also plays a role in microglia and can influence neuroinflammation. The next step is to investigate whether increasing microRNA-132 in neurons and microglia in a mouse model of Alzheimer’s has any actual effect.
“The same is true for the human cell lines we used. In this study, we only used a healthy control cell line, but we will run additional tests in Alzheimer’s cell lines to see if there are any effects.
Ultimate goal
“The ultimate goal would be to increase microRNA-132 in Alzheimer’s patients as a therapeutic strategy.” We are currently using viruses (containing microRNAs) in Alzheimer’s mice that can be injected intravenously, directly into the veins.
“This makes it easier to eventually transfer this strategy to the clinic because we’re using a virus that can theoretically be injected into the hand as well.”
“In addition to Alzheimer’s disease, there are other neurodegenerative diseases that show a decrease in the same microRNA. Therefore, these results may be relevant to other disease states.
For this research news on genetics and Alzheimer’s disease
Author: Elin Feenstra
source: KNOW
Contact: Elin Feenstra – I KNOW
Image: Image credit: Neuroscience News
Original research: Free access.
“microRNA-132 regulates gene expression programs involved in microglial homeostasis” by Evgenia Salta and others. Science
Summary
microRNA-132 regulates gene expression programs involved in microglial homeostasis
Accents
- MiR-132 is downregulated in Alzheimer’s disease (AD) brain.
- Mir-132, mainly known for neuronal functions, regulates many aspects of AD pathology
- Manipulation of MiR-132 in the mouse hippocampus reveals a role in microglial homeostasis
- MiR-132 shifts disease-associated to homeostatic microglia in iPSC-derived cultures
Summary
microRNA-132 (miR-132), a known neuronal regulator, is one of the most downregulated microRNAs (miRNAs) in the brain of Alzheimer’s disease (AD) patients. Increasing miR-132 in AD mouse brain ameliorates amyloid and tau pathologies and also restores adult hippocampal neurogenesis and memory deficits.
However, the functional pleiotropy of miRNAs requires a thorough analysis of the effects of adding miR-132 before it can be moved forward for AD therapy.
We employ here miR-132 loss- and gain-of-function approaches using single-cell transcriptomics, proteomics, and in silico AGO-CLIP datasets to identify molecular pathways targeted by miR-132 in mouse hippocampus.
We find that modulation of miR-132 significantly affects the transition of microglia from a disease-associated state to a homeostatic cellular state. We confirm the regulatory role of miR-132 in shifting microglial cell states using human microglial cultures derived from induced pluripotent stem cells.