Arc is Involved in Transmission of Tau Between Neurons in Alzheimer's Disease
The more severe later stages of Alzheimer's disease are characterized by altered forms of tau protein aggregating inside neurons to cause dysfunction, inflammation, and cell death. Researchers here show that tau can spread between neurons via extracellular vesicles, and identify the protein arc as necessary to this process. Once a mechanism involved in the spread of pathological proteins is developed, it is potentially a target for future therapies that might slow the progression of disease.
Neurodegenerative diseases are characterized by protein aggregation in specific brain regions that spread across the brain as the disease progresses. A major histopathological hallmark of Alzheimer's disease (AD) and tauopathies, such as frontotemporal dementia (FTD) and chronic traumatic encephalopathy, is intracellular neurofibrillary tangles that consist of misfolded tau protein. During aging, tau becomes hyperphosphorylated, resulting in misfolding and a decreased affinity for microtubules. Tau pathology is transmitted cell to cell, and the spread and levels of pathological tau strongly correlate with the degree of cognitive decline in AD patients.
We find that the neuronal gene Arc is critical for the release of tau in neuronal extracellular vesicles (EVs) via a direct protein-protein interaction. Brain extracellular vesicles (EVs) purified from transgenic rTg4510 mutant tau mice (rTgWT) crossed with Arc knockout mice (rTgArc KO) contain less tau and reduced tau seeding potential. Both Arc and tau are co-packaged in mouse and human brain-derived EVs. Moreover, Arc levels in brain-derived EVs isolated from human Alzheimer's disease (AD) brains show a strong positive correlation with phosphorylated EV-tau levels. rTgArc KO mice have increased accumulation of intracellular tau and a modest increase in cell toxicity early in disease progression. Strikingly, intercellular tau transmission is almost absent in Arc KO mice. These results show that Arc is critical for the packaging of tau in EVs, which plays a significant role in intercellular tau transmission.