Could tau protein accumulation be prevented by removing β-arrestin-2 oligomers?

Written by Alice Bough (Future Science Group)

Researchers from the University of South Florida (USF; FL, USA) have discovered that β-arrestin-2 oligomerization may disrupt the process by which neurotoxic tau proteins are removed from the brain.  

The authors of the study, published in the Proceedings of the National Academy of Sciences, suggest that β-arrestin-2 oligomers could be a new target for the prevention and treatment of dementia.

While the role of monomers of β-arrestin-2 is considered to be in regulating neurotransmitter receptors, little is known about the functions of oligomers of β-arrestin-2. To analyze whether either form of β-arrestin-2 has a role in the development of dementia, the researchers utilized cellular and mouse models to analyze its relationship with tau.

They demonstrated that in both cells and mice, an increased expression of tau protein coincided with an increased level of β-arrestin-2, while overexpression of β-arrestin-2 coincided with an increased level of tau.

“It has always been puzzling why the brain cannot clear accumulating tau” explained senior author of the study, Stephen Liggett (USF Health Morsani College of Medicine, FL, USA). “It appears that an ‘incidental interaction’ between β-arrestin-2 and the tau clearance mechanism occurs, leading to dementia.”

In mice that had been genetically designed to exhibit early tauopathy, which also had an inactivated β-arrestin-2 gene, it was observed that there was reduced tauopathy, synaptic dysfunction and loss of nerve cell connections when compared with β-arrestin-2 knockout mice.

“We also noted that decreasing β-arrestin-2 by gene therapy had no apparent side effects, but such a reduction was enough to open the tau clearance mechanism to full throttle,” continued Liggett. “This is something the field has been looking for – an intervention that does no harm and reverses the disease.”

You might also like:

Further investigation allowed the researchers to determine that it was the oligomerized version of β-arrestin-2 that caused the increase in tau protein levels. Blocking the protein’s ability to oligomerize reduced tau accumulation. They also established that the mechanism by which the oligomers act involves interactions with p62, a cargo protein that plays a role in the autophagy of tau proteins.

“This study identifies β-arrestin-2 as a key culprit in the progressive accumulation of tau in brains of dementia patients,” commented co-author, David Kang (USF Health Byrd Alzheimer’s Center, FL, USA). “It also clearly illustrates an innovative proof-of-concept strategy to therapeutically reduce pathological tau by specifically targeting β-arrestin oligomerization.”

The authors of the paper hope that inhibiting β-arrestin-2 oligomerization will not only be able to inhibit the development of new tau tangles, but also clear existing tau accumulations, potentially allowing both prevention and treatment of dementia.

“Our research could lead to a new strategy to block tau pathology in frontotemporal lobar degeneration, Alzheimer’s disease and other related dementias, which ultimately destroy cognitive abilities such as reasoning, behavior, language and memory,” concluded Jung-A Woo (USF Health Byrd Alzheimer’s Center), lead author of the paper.

Sources: Woo J-AA, Liu T, Fang CC et al. β-arrestin-2 oligomers impair the clearance of pathological tau and increase tau aggregates. Proc. Natl Acad. Sci. doi:10.1073/pnas.1917194117 (2020) (Epub ahead of print); https://hscweb3.hsc.usf.edu/blog/2020/02/17/beta-arrestin-2-increases-neurotoxic-tau-driving-frontotemporal-dementia/