Two separate research teams have published findings on distinct brain proteins that affect the accumulation and spread of tau protein, a substance linked to Alzheimer’s disease and other dementias. Both studies were published in the journal Cell.
Protein Arc Facilitates Tau Spread Between Neurons
A study led by researchers at the University of Utah Health and Washington University in St. Louis identified the brain protein Arc as a facilitator for the spread of toxic tau between neurons.
According to the study, Arc packages itself into extracellular vesicles (EVs) that travel between neurons. In Alzheimer’s disease, toxic tau attaches to Arc inside these vesicles, enabling its transfer from diseased to healthy neurons. In experiments on mice, those lacking Arc showed severely reduced tau transfer and decreased spread of pathology.
The researchers also noted that Arc may play a protective role early in the disease by helping neurons expel excess tau, reducing internal toxicity.
Extracellular vesicles containing both Arc and tau were found in human brain tissue, suggesting a similar mechanism may occur in humans, though further research is needed.
The study’s first author was Mitali Tyagi, PhD, and the senior author was Jason Shepherd, PhD. The research was supported by the National Institutes of Health, the Chan-Zuckerberg Initiative, and the Alzheimer’s Association.
Protein CUL5 Identified as Key Regulator of Tau Clearance
A separate study by researchers at UC San Francisco identified the brain protein CUL5, which functions to dispose of toxic tau clumps inside neurons. Neurons with higher levels of CUL5 showed reduced vulnerability to Alzheimer’s disease.
The research team developed a petri-dish model of human neurons engineered to produce tau clumps. Using CRISPR gene editing, they disabled each of the cells’ 20,000 genes individually to observe effects on tau clump formation. The screening process identified CUL5, which was found to tag tau for elimination before it could form clumps.
To confirm the findings in human subjects, researchers analyzed data from the Seattle Alzheimer’s Disease Brain Atlas, which contains brain samples from deceased Alzheimer’s patients. Brain cells showing resistance to degeneration in these patients contained high levels of CUL5, supporting its role in preventing tau clumping.
The study also identified a set of genes related to oxidative stress that influenced tau accumulation. Oxidative stress, a process that damages cells and increases with age, was observed to make tau more prone to clumping.
The senior author was Martin Kampmann, PhD, and the lead author was Avi Samelson, PhD. The research was published in Cell on January 28th.
Potential Therapeutic Implications
The findings from both studies suggest potential pathways for therapeutic development.
- The research on Arc points to the possibility of intercepting tau-containing extracellular vesicles to slow disease progression.
- The research on CUL5 points to the possibility of enhancing the body’s natural mechanism for clearing tau to prevent neurodegeneration.
Both teams noted that further research is required to determine if these mechanisms can be translated into treatments for humans.