Two science journals pointed out that blocking the TGF - β receptor in astrocytes is promising for the treatment of Alzheimer's disease and epilepsy

December 26, 2019 / Biovalley BIOON / - -- drugs that inhibit brain inflammation may slow or even reverse cognitive decline with age In the first new study, Dr Daniela Kaufer, Professor of integrative biology, University of California, Berkeley, and alon, University of bangulion, Israel Dr Friedman and colleagues report that older mice given one of these drugs show fewer signs of brain inflammation and are better able to learn new tasks, almost as skilled as mice half their age The related research results were recently published in the Journal of Science Translational Medicine The title of the paper is "blood brain barrier dysfunction in aging causes hyperactivation of TGF β signaling and chronic yet reversible natural dysfunction" The picture is from alon Friedman and Daniela Kaufer "We tend to look at aging brains in a way that looks at neurodegeneration: aging involves loss of function and cell death," said Daniel Kaufer, a communications author and professor of integrative biology at the University of California, Berkeley But our new data explains why aging brains don't work well in a different way: it's because of this' fog 'of inflammatory load But when the inflammatory fog is removed, the old brain is like the young brain for a few days In terms of the plasticity of the brain, this is a very, very optimistic discovery We can reverse brain aging " The success of this treatment in mice supports a whole new idea of what causes the mental disorders and dementia that often accompany aging More and more studies have shown that with the increase of age, the filtration system (so-called blood-brain barrier) that prevents molecules or infectious organisms in the blood from infiltrating into the brain leaks, which causes serious and a series of cell death chemicals to enter the brain According to Friedman's magnetic resonance imaging (MRI) study, after the age of 70, nearly 60% of adults have a blood-brain barrier with leakage In a second new study, Kaufer, Friedman and Dan of the University of bangulion Milikovsky and his colleagues found that the inflammatory mist caused by the leaky blood-brain barrier changed the normal rhythm of the mouse brain, leading to an event similar to a microepileptic attack, namely a brief pause of the normal rhythm in the hippocampus, which may produce some symptoms in degenerative brain diseases such as Alzheimer's disease Electroencephalogram (EEG) shows that there are similar brain wave interference or paroxysmal slow wave events in people with epilepsy and cognitive dysfunction (including Alzheimer's disease and mild cognitive impairment) The related research results were recently published in the Journal of Science Translational Medicine, and the title of the paper is "paroxysmal slow critical activity in Alzheimer's disease and epilepsy is associated with blood brain barrier dysfunction" In conclusion, these two papers provide doctors with two biomarkers - blood brain barrier leakage detected by MRI and abnormal brain rhythm detected by EEG - which can be used to indicate people with blood brain barrier problems and potential drugs that can slow or reverse these consequences "We now have two biomarkers that tell you exactly where the blood-brain barrier is leaking, so you can choose the patients you want to treat and decide how long to give them," Kaufer said You can follow the drug regimen, when the BBB leakage is cured, you no longer need the drug " For a long time, scientists have been guessing that the leakage of blood-brain barrier will cause some tissue damage at least after brain damage, and will lead to some mental decline with age But no one knows how In 2007, however, Friedman and Kaufer linked these problems to a blood protein called albumin In 2009, they found that albumin binds to the TGF - β receptor in brain cells called astrocytes when it penetrates the brain after trauma This will cause a series of inflammatory reactions, damage other brain cells and neural circuits, resulting in decreased neuronal inhibition, increased neuronal excitability and seizure tendency They also found in mice that blocking the TGF - β receptor with losartan, an antihypertensive drug, prevented seizures after brain trauma Epilepsy is a common consequence of concussion Subsequent studies revealed blood-brain barrier leakage after stroke, traumatic brain injury, and soccer concussion, which strongly linked albumin and overactivated TGF - β receptor to the trauma In both new studies, Kaufer and Friedman found that the introduction of albumin into the brain made the brain of young mice look like old mice in terms of hyperactivity and susceptibility to epilepsy within a week These mice treated with albumin were just as difficult to get out of the maze as old mice "When we injected albumin into the brain of young mice, we reproduced aging in the following areas: gene expression, inflammatory response, adaptability to induced epilepsy, post seizure mortality, and performance in mazes," Kaufer said When we record their brain activity, we find these paroxysmal slow wave events All of this is limited to the sites where we inject albumin So that's enough to get the aging phenotype of this very young brain " After they genetically engineered mice that reached old age to knock out the TGF - β receptor in their astrocytes, the brains of these old mice looked younger These mice had the same resistance to induced epilepsy as young mice, and learned to walk out of the maze as young mice Barry Hart, a chemical pharmacist in Palo Alto, California, inadvertently proposed the synthesis of a small molecule drug that can only block the TGF - β receptor in astrocytes and cross the blood-brain barrier When they gave older mice a drug called IPW, the doses lowered their TGF - β receptor activity levels to levels in younger mice, and the brains of these older mice also looked younger They show gene expression similar to young brains, reduced inflammation and improved brain rhythms (i.e., decreased paroxysmal slow wave events), and decreased susceptibility to epilepsy They also walked out of mazes or learned space tasks like young mice When analyzing brain tissue from humans, Kaufer found evidence that albumin is present in the old brain next year, and that neuroinflammation and TGF - β production increase with age Friedman developed a special type of MRI - dynamic contrast-enhanced (DCE) imaging - to detect leakage in the blood-brain barrier, and found that people with greater cognitive impairment had more blood-brain barrier leakage Overall, Kaufer, the evidence suggests that dysfunction of the brain's blood filtration system was one of the first triggers of neural aging Kaufer, Friedman and Hart have set up a company to develop a drug to cure the blood-brain barrier clinically, and hope that the drug will help reduce the brain inflammation after stroke, concussion or brain trauma, thus reducing the resulting permanent damage, and ultimately help Alzheimer's or Alzheimer's patients with bleeding brain barrier leakage (BIOON Com) reference: 1 Vladimir v senatorov Jr et al Blood brain barrier dysfunction in aging causes hyperactivity of TGF β signaling and chronic yet renewable natural dysfunction Science Translational Medicine, 2019, DOI: 10.1126/scitranslmed.aaw8283 2 Dan Z milikovsky et al Paroxysmal slow critical activity in Alzheimer’s disease and epilepsy is associated with blood-brain barrier dysfunction Science Translational Medicine, 2019, doi:10.1126/scitranslmed.aaw8954 3.Drugs that quell brain inflammation reverse dementia https://medicalxpress.com/news/2019-12-drugs-quell-brain-inflammation-reverse.html