Brain protein tied to Alzheimer’s spread in mouse study

Researchers at University of Utah Health say a protein best known for helping brain cells communicate appears to help Alzheimer’s-related tau move from damaged neurons into healthy ones. The finding, reported in the journal Cell, could give scientists a new target for slowing how the disease advances through the brain.

Alzheimer’s disease is associated with the buildup of tau, a protein that can form harmful tangles inside neurons. As tau pathology reaches more parts of the brain, memory and thinking problems worsen, according to University of Utah Health.

The research team focused on Arc, a protein that normally supports communication between neurons. In mouse models of Alzheimer’s disease, the scientists found that Arc helped package tau into extracellular vesicles, tiny membrane-bound sacs that cells use to send material to other cells.

Jason Shepherd, a professor of neurobiology at University of Utah Health and senior author of the study, said the work identifies a possible new way to stop Alzheimer’s progression. The approach would aim to block tau from reaching healthy neurons rather than remove all tau from the brain.

How tau appears to move

According to the study, Arc can assemble inside extracellular vesicles that travel between neurons. The researchers reported that harmful tau can attach to Arc within those vesicles, allowing tau to leave a sick neuron and enter a healthy one.

Mitali Tyagi, the study’s first author and a postdoctoral research associate at Washington University in St. Louis, conducted the work while in Shepherd’s lab. She described tau tangles as sticky clumps that disrupt transport inside neurons and said smaller tau “seeds” can start the same process in a new cell after transfer.

In Alzheimer’s mouse models, the team found extracellular vesicles in brain tissue that contained both Arc and sticky tau. Those vesicles could enter healthy cells and trigger new tau tangles, according to University of Utah Health.

When the researchers removed Arc from the mouse model, the vesicles carried very little tau, and tau transfer to nearby brain cells fell sharply. Tyagi said the movement of tau was “severely” reduced and “almost gone” when Arc was absent.

A difficult target

The findings also showed why directly blocking Arc could be complicated. University of Utah Health said Arc appeared to help diseased neurons survive longer by allowing them to expel excess toxic tau.

Without Arc, tau stayed trapped inside neurons and rose to toxic levels, causing already damaged cells to die faster, according to Tyagi. With Arc present, neurons could release tau in vesicles, but those same vesicles could carry the pathology to neighboring healthy cells.

That result led the researchers to suggest a more precise strategy: intercept tau-carrying extracellular vesicles after they leave sick neurons but before they enter healthy ones. Such a treatment would not undo existing brain damage, but Shepherd said it could be useful if it stops further spread and cognitive decline in people with early Alzheimer’s or dementia.

Human relevance remains uncertain

The team also detected extracellular vesicles containing both Arc and tau in human brain tissue, suggesting a similar process could occur in people. Shepherd cautioned that most of the work was done in mice and that the researchers do not yet know whether the mechanism operates the same way in humans.

The study, “Arc mediates intercellular tau transmission via extracellular vesicles,” was published in Cell. University of Utah Health said the work was supported by the National Institutes of Health, the Chan-Zuckerberg Initiative, the Alzheimer’s Association and other funders; human samples came from the Massachusetts Alzheimer’s Disease Research Center.

University of Utah Health also disclosed that Shepherd co-founded VNV, LLC and holds stock in and consults for Aera Therapeutics, which licenses intellectual property and patents that include Arc capsids.

This story draws on original reporting from ScienceDaily.