How Brain Inflammation Affects Alzheimer’s And Cognitive Decline
Small interfering RNAs can inhibit the translation of specific mRNAs, allowing them to halt the synthesis of particular proteins. Scientists have explored the potential of using this approach to decrease neuroinflammation, which is characterised by inflammation in the brain, by preventing the production of a specific protein known to have a significant role in this process.
The delivery method they created for this purpose might also find application in future studies aimed at deactivating specific genes in microglia.
Small interfering RNAs, or siRNAs, focus on how mRNA helps create proteins in our body. mRNA is crucial in turning our DNA instructions into the proteins our body requires.
A challenge in developing drugs is that a lot of them can only move around in the bloodstream. This makes it tricky to reach the brain because of something called the blood-brain barrier. As a result, treating neurological conditions like Alzheimer's disease can be pretty challenging.
Brain Inflammation In Alzheimer’s Disease
Even though Alzheimer's disease is becoming more common, there are still no effective treatments available. This year, the European Medicines Agency (EMA) approved a drug called aducanumab, even though there isn't strong evidence of its effectiveness.
While many researchers focus on beta-amyloid as a primary target, other potential targets for new drugs are being considered. Previous research has shown that inflammation is a significant factor in neurodegenerative disorders like Alzheimer's disease.
Several studies have connected brain inflammation in Alzheimer's to a protein called PU.1, which switches genes on and off. Interestingly, many parts of our genetic code linked to Alzheimer's risk are connected to genes controlled by PU.1.
This protein is mainly found in microglia immune cells in the brain, and it plays a crucial role in controlling the genes necessary for microglia to function correctly.
Reducing Inflammation In The Brain
Researchers have created a drug using siRNA to disrupt PU.1, aiming to decrease inflammation in microglial cells. Their study and the development of a new delivery method for siRNA are detailed in Advanced Materials.
These researchers, affiliated with MIT, have previously demonstrated that inhibiting the PU.1 protein can reduce inflammation. This study showed that delivering siRNA to microglial cells can lower PU.1 levels.
The focus of their work is on addressing brain inflammation (neuroinflammation), a well-known characteristic of Alzheimer's disease and many other neurodegenerative conditions. When neurons die, and harmful aggregates like beta-amyloid plaques or prions spread in the diseased brain, the brain's immune system, primarily composed of microglia, becomes activated.
Persistent neuroinflammation can lead to long-term damage to brain cells. By reducing neuroinflammation, the researchers aim to halt the disease's progression and provide the brain with an opportunity to recover from the initial causes of the disease, ultimately restoring the patient's normalcy.
Nanoparticle Delivery System For Experimental Therapy
Researchers have developed a particular RNA, siRNA, to stop the production of a protein called PU.1. The challenge was getting this siRNA into the cells, specifically the microglia. They created seven different formulations using tiny lipid nanoparticles (LNP) to deliver the siRNA into the cells. LNPs were utilised in the COVID-19 vaccine from Pfizer, so they are known to be safe and effective.
To determine which LNP worked best, they tested them on lab-grown human microglia-like cells. They attached a marker to the siRNA to see which LNP got the most siRNA into the cells. They found one LNP formula was the most effective.
Next, they tested how to get past mice's protective barrier around the brain, called the blood-brain border. They injected the siRNA into the mice's bloodstream and the fluid around the brain and spine. The injection into the brain fluid worked best at reaching the microglia.
It uses siRNA to block PU.1 and Reduces brain inflammation, almost like in normal mice without Alzheimer's disease. This approach looks promising for developing treatments to reduce brain inflammation.
One of the researchers explained that they made a unique formula to deliver siRNA into specific cells, and it's well-tolerated and effective. This method can target almost any gene using siRNA.
A scientist who was not part of the study mentioned that reducing brain inflammation is a promising approach in Alzheimer's disease research because too much inflammation is a significant risk factor.
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