Brain messenger protein Arc identified as vehicle for Alzheimer's toxic spread, pointing to a new class of therapy

Researchers at the University of Utah Health have identified a brain protein best known for its role in memory as the molecular vehicle that carries toxic Tau from diseased neurons to healthy ones — a discovery that could reshape how therapies for Alzheimer's disease are designed, according to a study published on Sunday 29 June in the journal Cell.

Alzheimer's disease is driven by a buildup of a toxic protein called Tau that kills neurons, and as toxic Tau spreads to new regions of the brain, symptoms become worse and ultimately fatal. While scientists have long understood that Tau spreads from diseased cells to healthy neighbours, the exact molecular vehicle responsible for this intercellular transmission had remained a critical mystery in neurodegeneration.

The Arc connection

Arc — formally the Activity-regulated cytoskeleton-associated protein — is encoded by the immediate-early gene arg 3.1 and plays a critical role in stabilising activity-dependent hippocampal plasticity and cognitive processes such as memory formation. Arc normally serves as a vital messenger between brain cells: it wraps itself in a microscopic bubble, called an extracellular vesicle (EV), that floats from one neuron to the next, carrying important information.

But toxic Tau can stick to Arc to hitch a ride from a diseased neuron to a healthy one. All brain cells, healthy and unhealthy, contain Tau; but in Alzheimer's disease, Tau starts clumping together into massive, sticky tangles inside neurons, ultimately killing the cells.

In mouse models, removing Arc sharply reduced the transfer of Tau between brain cells, pointing to a potential new strategy for slowing disease progression rather than reversing damage that has already occurred.

A double-edged role

The finding carries an important complication. The researchers found that in mice lacking Arc, which therefore cannot eject toxic Tau from sick cells, those sick cells die faster. Blocking Arc entirely would therefore accelerate neuron death in the very cells the therapy aims to protect.

The research team's proposed solution is more precise: target the extracellular vesicles themselves, rather than Arc as a whole. "If we could target these particular EVs, that would be a really useful therapy strategy," said Jason Shepherd, PhD, professor of neurobiology at University of Utah Health and senior author of the study. "For someone with early-onset Alzheimer's or dementia, if we could stop the spread, then we could prevent further damage and cognitive decline."

The discovery points to a possible new strategy for slowing Alzheimer's disease: rather than trying to eliminate Tau entirely, future treatments might stop it from reaching healthy brain cells in the first place.

Scope and limits

The study was conducted entirely in mice, using a transgenic model that carries a mutant Tau gene; the mechanisms of intercellular Tau transmission remain to be fully characterised. The findings have not yet been replicated in human tissue in a clinical setting, and no drug candidate has been identified. Human samples were provided by the Massachusetts Alzheimer's Disease Research Center, supported by the National Institute on Aging, for supporting analyses.

Shepherd disclosed that he is a co-founder of VNV, LLC and holds stock in and is a consultant for Aera Therapeutics, Inc., which licenses intellectual property and patents that include Arc capsids. The paper is published open access under a Creative Commons Attribution 4.0 licence.

Why this matters in the region

Dementia prevalence among those aged over 60 is among the highest in the Arab world in Tunisia, at 4.43 percent, alongside Lebanon and Algeria. Projections from Tunisian epidemiological research had estimated that by 2030 around 58,000 people aged 65 and over would be living with dementia syndromes in the country, of whom nearly 40,600 would have Alzheimer's disease. Alzheimer's disease and other dementias will be a major challenge that Tunisia will face in coming years, in terms of health, society and the economy.

The estimated global number of people living with dementia was 57.6 million in 2021, with approximately 10 million new cases diagnosed each year, and the number is projected to reach 152.8 million cases by 2050.

The paper, titled "Arc mediates intercellular tau transmission via extracellular vesicles", was authored by Mitali Tyagi, Eric de Hoog, Matthew Grega and colleagues at the University of Utah, the Max Planck Institute of Biophysics, the University of Padova, and Massachusetts General Hospital/Harvard Medical School. Funding came from the National Institutes of Health, the Chan-Zuckerberg Initiative, the Alzheimer's Association, the McKnight Brain Disorders Award, the Max Planck Society, the Rainwater Foundation, the JPB Foundation and the Cure Alzheimer Fund.