The two primary hallmarks of Alzheimer’s disease are clumps of sticky amyloid-beta (Aβ) protein fragments known as amyloid plaques and neuron-choking tangles of a protein called tau. Abnormal accumulations of both proteins are needed to drive the death of brain cells, or neurons, in Alzheimer’s, although the tau accumulations now appear to correlate better with cognitive dysfunction than Aβ, and drugs targeting Aβ have been disappointing as a treatment. A new study by the University of South Florida Health (USF Health) Morsani College of Medicine, has found that a protein called β-arrestin-2 increases the accumulation of neurotoxic tau tangles, a cause several forms of dementia, by interfering with removal of excess tau from the brain, The USF Health researchers discovered that a form of the protein comprised of multiple β-arrestin-2 molecules, known as oligomerized β-arrestin-2, disrupts the protective clearance process normally ridding cells of malformed proteins like disease-causing tau. Their findings are now published in the prestigous journal Proceedings of the National Academy of Sciences (PNAS).
The study focused on frontotemporal dementia (FTD), a neurodegenerative disorder second only to Alzheimer’s disease as the leading cause of dementia. This aggressive, typically earlier onset dementia (ages 45-65) is characterized by atrophy of the front or side regions of the brain, or both. Aβ aggregation is absent in the FTD brain, where the key neurodegeneration feature appears to be excessive tau accumulation, known as tauopathy. The resulting neurofibrillary tangles (twisted fibers laden with tau) destroy synaptic communication between neurons, eventually killing the brain cells. Like Alzheimer’s disease, FTD displays an accumulation of tau, and has no specific treatment or cure. Monomeric β-arrestin-2 is mostly known for its ability to regulate receptors, molecules on the cell that are responsible for hormone and neurotransmitter signaling. β-arrestin-2 can also form multiple interconnecting units, called oligomers. The function of β-arrestin-2 oligomers is not well understood. Monomeric β-arrestin-2, the protein’s single-molecule form, does not impair this cellular toxic waste disposal process known as autophagy.
This form was the basis for the laboratory’s initial studies examining tau and its relationship with neurotransmission and receptors, but soon researchers became transfixed on these oligomers of β-arrestin-2. Lab experiments allowed the team to see that both in cells and in mice with elevated tau, β-arrestin-2 levels are increased. Furthermore, when β-arrestin-2 is overexpressed, tau levels increase, suggesting a maladaptive feedback cycle that exacerbates disease-causing tau. Moreover, genetically reducing β-arrestin-2 lessens tauopathy, synaptic dysfunction, and the loss of nerve cells and their connections in the brain. For this experiment researchers crossed a mouse model of early tauopathy with genetically modified mice in which the β-arrestin-2 gene was inactivated, or knocked out. The researchers blocked β-arrestin-2 molecules from binding together to create oligeromized forms of the protein. They demonstrated that pathogenic tau significantly decreased when only oligomeric β-arrestin-2, which does bind to receptors, was present. In addition, oligomerized β-arrestin-2 increases tau by impeding the ability of cargo protein p62 to help selectively degrade excess tau in the brain.
In few words, this reduces the efficiency of the autophagy process needed to clear toxic tau, so tau “clogs up” the neurons. Blocking of β-arrestin-2 oligomerization suppresses disease-causing tau in a mouse model that develops human tauopathy with signs of dementia. Jung Alexa Woo, PhD, paper’s lead author, assistant professor of molecular pharmacology and physiology and an investigator at the USF Health Byrd Alzheimer’s Center, explained: “Our research could lead to a new strategy to block tau pathology in FTLD, Alzheimer’s disease and other related dementias, which ultimately destroys cognitive abilities such as reasoning, behavior, language, and memory. It has always been puzzling why the brain cannot clear accumulating tau. It appears that an ‘incidental interaction’ between β-arrestin-2 and the tau clearance mechanism occurs, leading to these dementias. β-arrestin-2 itself is not harmful, but this unanticipated interplay appears to be the basis for this mystery. This study identifies beta-arrestin-2 as a key culprit in the progressive accumulation of tau in brains of dementia patients. It also clearly illustrates an innovative proof-of-concept strategy to therapeutically reduce pathological tau by specifically targeting beta-arrestin oligomerization”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Woo JA et al. Proc Natl Acad Sci USA 2020 Feb 17.
Oishi A et al. ACS Sensors 2020 Jan 24; 5(1):57-64.
Bangasser DA et al. Mol Psychiatry 2017; 22(8):1126.
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