Why do brain cells die? Study offers new clues

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  • About 32 million people globally have Alzheimer’s disease.
  • While scientists are still unclear as to the true cause of Alzheimer’s disease, they do know a loss of neurons in the brain plays an important role.
  • A new study from researchers at Northwestern University has found a possible new cause of neuron death in Alzheimer’s through toxic RNA strands.

Alzheimer’s disease is the most common form of dementia and is estimated to affect about 32 million people worldwide.

While scientists are still unclear as to the true cause of Alzheimer’s disease, they do know a loss of neurons in the brain plays an important role.

Now, in a new study published in the journal Nature Communications, researchers from Northwestern University have found a possible new cause of neuron death in Alzheimer’s through toxic RNA strands.

Medical News Today spoke with Dr. Marcus Peter, Ph.D., the Tom D. Spies Professor of Cancer Metabolism at Northwestern University Feinberg School of Medicine and senior author of this study. Dr. Peter told MNT that he and his team decided to focus on what causes brain cell loss in Alzheimer’s disease after discovering a novel and powerful anti-cancer mechanism a few years ago.

“We hypothesized that this mechanism, while powerful in killing cancer cells, may also under certain circumstances kill normal cells,” Dr. Peter explained. “We were looking for diseases that are characterized by cell loss — such as neurodegenerative diseases — and we predicted that patients suffering from such diseases would have lower cancer rates.”

“We found it in Alzheimer’s disease as it has been described multiple times that Alzheimer’s disease patients have less cancer. So we tested whether our original anti-cancer kill code was contributing to Alzheimer’s disease pathology and found ample evidence for that.”

– Dr. Peter

For this study, Dr. Peter and his team analyzed the brains of several sources, including mouse models of Alzheimer’s disease, stem cell-derived neurons for both people with and without Alzheimer’s, and older adults over age 80 with memory capacity equivalent to individuals 50 to 60 years old.

During the study, researchers focused on RNA and how it might contribute to brain cell death.

According to Dr. Peter, every person has different classes of RNA in all their cells, and two of them are most relevant to this study’s findings.

“The first class is long RNAs — so-called messenger (m)RNAs — that code for the proteins that make all our cells function,” he explained. “They are being converted into proteins. mRNAs are hundreds or thousands of nucleotides long.”

The second class is short (s)RNAs, which Dr. Peter said are 19-22 nucleotides in length.

“This class acts by suppressing the activity of the long mRNAs,” he added. “That results in the block of converting the long mRNAs into proteins.”

During previous research, Dr. Peter and his team found a code embedded in the short RNAs that are just six nucleotides long.

“When this sequence is present at a certain position of these sRNAs, they kill all cells,” he detailed. “We called the short sequence the ‘kill code.’ Cells die because sRNAs that carry the code selectively suppress mRNAs that code for proteins that (are) critical for the survival of all cells.”

“Just like we have organs we cannot live without (i.e., the heart), cells have proteins they cannot live without. sRNAs that carry the kill code suppress such proteins and cells die.

Interestingly, the sRNAs that carry the kill code can be balanced out by sRNAs that do not carry the kill code. They act as protectors when present (in) large quantities.”

– Dr. Peter

Dr. Peter said their model now predicts that in any normal cell, there are enough protective sRNAs to balance out the toxic ones.

“Brain cells are also protected by these nontoxic sRNA, but are particularly susceptible to the toxic sRNAs,” he continued. “We now show that with age, the amount of protective sRNAs goes down and that of toxic ones goes up. That should happen (to) all of us.”

“However, when there are higher amounts of toxic RNAs present then at a certain age the protection will not be sufficient enough anymore, and pathology can emerge.” Dr. Peter added. “The toxic sRNAs can now kill the neurons.”

For many years, the common consensus among researchers is that clumps of beta-amyloid proteins called plaques and tau proteins called tangles within the brain are the main cause of Alzheimer’s disease.

“These proteins are certainly involved and important,” Dr. Peter said. “However, it could never be shown how exactly they result in the death of neurons. Our work now provides a new model for how that occurs. The toxic sRNAs are downstream of these two proteins. We believe that they are the executioners.”

When asked if these new RNA-based findings might result in new treatments for Alzheimer’s disease, Dr. Peter said this new avenue still needs to be explored:

“In our paper, we show that stabilizing or increasing the amount of protective sRNAs or inhibiting the toxic sRNAs can rescue cells from cell death. This provides new avenues for drug development to treat AD and potentially other neurodegenerative diseases.

“(Research next steps include) testing our concept in more animal models and in Alzheimer’s disease patients derived neurons and postmortem brain tissues,” Dr. Peter continued. “Then screening and testing for drugs that either increase the level of the protective sRNAs or reduce the activity of the toxic ones. There are concepts and ideas that need to be and can be tested now.”

After reviewing this study, Dr. Karen D. Sullivan, a board certified neuropsychologist, owner of I CARE FOR YOUR BRAIN, and Reid Healthcare Transformation Fellow at FirstHealth of the Carolinas in Pinehurst, NC, told MNT that the insights gained from this study give us a better understanding of both what goes very wrong in the aging brain via Alzheimer’s disease and what goes very right in the aging brain with SuperAgers.

“It also gives hope for a novel intervention pathway to stop or slow down this devastating neurodegenerative disease,” Dr. Sullivan continued. “Over 90% of current Alzheimer’s disease research efforts focus on the compounds amyloid and tau. This study suggests that another disease process, RNA, may be a target for future treatments.”

MNT also spoke about the study with Dr. Clifford Segil, a neurologist at Providence Saint John’s Health Center in Santa Monica, CA.

Dr. Segil said he is cautiously optimistic that RNA-based therapies that are being introduced for many diseases will have good clinical neurological applications.

“This study clearly showed that there is neurotoxicity related (to) the genes that they looked at,” he continued. “The study is also trying to state that there (are) neuroprotective benefits from these types of medications and other disease states.”

“I’m hopeful that something like an mRNA-based therapy can be neuroprotective in humans, given the right research in other animals working up to humans one day,” Dr. Segil added. “I think it’s optimistically cautious.”

Read the full article here

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