Understanding the Role of Labeled RNA Molecules Seen to Increase in Alzheimer's Disease Could Pave the Way for New Drugs!

Understanding the role of the tau protein in Alzheimer's disease has led to new ways of diagnosing the disease, as well as the creation of drugs that are currently in clinical trials to treat the disease.

Misfolding and aggregation of the microtubule-associated protein tau (MAPT) are key features of Alzheimer's. As neurons become diseased, they show characteristic changes, such as the accumulation of neurofibrillary tangles made up of misfolded tau protein. Tau accumulation is closely associated with cognitive decline in Alzheimer's patients.

Yet neurofibrillary tangles are only a part of Alzheimer's pathology, and scientists are trying to understand how injury to nerve cells leads to neurofibrillary tangles in order to develop the best drugs and diagnoses for Alzheimer's. Now, researchers from the Boston University School of Medicine (BUSM) have discovered a new type of molecular pathology that accumulates in the nerve cells of Alzheimer's patients.[1] Corresponding author, Professor of pharmacology and experimental therapeutics at BUSM. Benjamin Wolozin says:

We found that as injured nerve cells accumulate misfolded tau protein, they put a tag on RNA, the genetic material that encodes the proteins. The amount of labeled RNA, called N6-Methyladenosine (m6A), increases approximately fourfold during the course of the disease.

Wolozin and his researchers then went on to investigate why these RNA tags accumulate with disease. The group used optogenetics combined with protein analysis to explore how misfolded tau specifically binds RNA with these tags (genes for photosensitive proteins were introduced into specific brain cell types to precisely monitor and control their activity using light signals). and it did so with the help of another RNA-binding protein called HNRNPA2B1 (which is also linked to a type of brain degeneration called amyotrophic lateral sclerosis).

Wolozin demonstrated that binding of misfolded tau or HNRNPA2B1 is required for the entire complex to exhibit biological actions; genetic knockdown of both strains blocked neurodegeneration and also reduced the amount of tagged RNA accumulated. The team hypothesizes that this complex is specialized to respond to injury, but in Alzheimer's the response becomes hyperactive, persistent, and therefore harmful. Wolozin says:

This work opens up a new avenue that researchers can use to study the Alzheimer's process, and in the process, perhaps develop new approaches to treat the disease.