Alzheimer's risk: Researchers look for ways to lower neuroinflammation

• Small interfering RNAs can silence the machinery that translates certain mRNAs, meaning they can also be used to stop the production of some proteins.
• Researchers have looked at the possibility of reducing neuroinflammation — inflammation in the brain — by stopping the translation of a particular protein known to play a key role.
• The delivery system they developed for it could be used in future research looking at knocking out certain genes in microglia.

Small interfering RNAs (siRNAs) target the process by which mRNAs are translated into proteins. mRNA is involved in the translation of DNA, and codes for the proteins that the body needs to make.

One limitation in drug development is that many drugs only travel through the bloodstream, meaning it is difficult to get them to the brain, due to the blood-brain barrier.

This can make treating neurological conditions, including Alzheimer’s disease, difficult.

Brain inflammation in Alzheimer’s disease

Despite the fact that Alzheimer’s disease is becoming an increasingly prevalent condition, there are still no effective treatments for it.

This year saw the Food and Drug Administration (FDA) approve the drug aducanumab, which targets beta-amyloid — a key marker of dementia — despite a lack of evidence for its efficacy.

While beta-amyloid remains the primary target for many researchers, there are other potential drug targets that researchers are considering.

Previous research has shown that inflammation is a hallmark of neurodegenerative disorders, including Alzheimer’s disease.

Many studies have linked the neuroinflammation seen in Alzheimer’s disease to a transcription factor — a protein that turns genes on and off — called PU.1.

In fact, many of the areas of the genome associated with variants that can affect risk of Alzheimer’s disease code for genes regulated by PU.1. It is largely expressed in the microglia, immune cells that exist in the brain, and regulates the expression of genes essential for microglia function.

Reducing inflammation in the brain

Now, a team of researchers has developed a drug using siRNA that interrupts PU.1, in an attempt to reduce inflammation in microglial cells.

The results of their study appear in Advanced Materials, along with discussion about how they developed a new delivery mechanism to get the siRNA into the microglial cells.

In this study, researchers from MIT who have previously shown that inflammation can be decreased by inhibiting the PU.1 protein, showed that siRNA delivered to the microglia could reduce PU.1 expression.

One of the lead authors, Dr. Owen Fenton, assistant professor in the Eshelman School of Pharmacy at the University of North Carolina at Chapel Hill told Medical News Today:

“We target the inflammation of the brain (neuroinflammation) as it is a well-known hallmark of Alzheimer’s disease. Neuroinflammation can further be seen in virtually all neurodegenerative diseases. The immune system of the brain, mainly composed of microglia, becomes activated as neurons start dying and as pathological aggregates — such as [beta-amyloid] plaques or prions — spread throughout the diseased brain.“

“A persistent state of neuroinflammation can in the long-term cause damage to brain cells. By reducing neuroinflammation, we seek to stop the disease from progressing and also give the brain a chance to recover from the initial cause of the disease and, ultimately, to bring the patient back to normalcy,” he further explained.

Nanoparticle delivery system for experimental therapy

Researchers developed an siRNA that would interrupt the production of PU.1 protein. However, the challenge they then needed to overcome was how to get the siRNA inside the cell where it would interrupt mRNA and, specifically the microglia.

They developed seven lipid nanoparticle (LNP) formulations to carry the siRNA they had developed into the cells. LNP formulations have already been used in Pfizer’s mRNA COVID-19 vaccine, and have been shown to be safe and effective.

To determine which of the LNP formulations they had developed was the most effective at getting the siRNA into the nucleus of the cell they tested them on in vitro cultures of human stem cell-derived microglia-like cells (iMGLs).

They tagged the siRNAs so they could be imaged to see which LNP formulations resulted in the highest concentration of siRNAs in the IMGLs. They identified one of their LNP formulations as the most effective on iMGLs.

To test the best way to get past the blood-brain barrier, researchers then carried out experiments on mice. They injected the mice normally into the bloodstream or into the cerebrospinal fluid which runs between the spine and space between the skull and the brain. They found injection into cerebrospinal fluid was the most effective at being absorbed by the microglia.

They found that using siRNA to disrupt PU.1 reduced inflammation to levels almost as low as that seen in control mice, making it a promising target for anti-inflammatory siRNA therapeutics, authors said.

Dr Fenton explained: “Our approach relies on delivering siRNA into specific cells, necessitating a stable, targeted, and well-tolerated formulation. Our formulation was precisely engineered to possess these properties to enable efficient and effective siRNA delivery.“

He added that “[v]irtually any gene can be targeted with siRNA using this system.”

Dr. Jennifer Bramen, senior research scientist at the Pacific Neuroscience Institute in Santa Monica, CA, who was not involved in the research, commented on the study for MNT, noting that:

”[E]xcessive neuroinflammation is a major risk factor in Alzheimer’s disease. Reducing neuroinflammation to treat [Alzheimer’s disease] is an active and promising area of research.”

Source: Read Full Article