Arc Protein Mediates Tau Spread via Extracellular Vesicles in Alzheimer's Mouse Models

Researchers at University of Utah Health used an Alzheimer's mouse model with and without Arc to demonstrate that the protein packages toxic Tau into extracellular vesicles for intercellular transfer. In Arc-deficient animals, brain EVs carried minimal Tau and lost the ability to propagate pathology, while human postmortem tissue confirmed similar Arc-Tau EV complexes. This mechanism explains how Tau seeds corrupt healthy Tau after release from dying neurons.

The dual role of Arc creates a therapeutic tension: its presence ejects excess Tau from sick cells, prolonging their survival, yet enables spread to neighboring neurons. Removing Arc accelerated intraneuronal Tau accumulation and cell death, indicating that blocking uptake rather than release may be the safer intervention point. This pattern aligns with prior observations of EV-mediated propagation in other proteinopathies such as frontotemporal dementia.

Future work must test whether Arc-Tau binding inhibitors can decouple release from uptake in human neurons without disrupting Arc's normal synaptic functions. Longitudinal studies in non-human primates will be required to establish dosing windows before clinical translation.