Amyloid beta is the cause of Alzheimer's disease!

In a new preclinical study, researchers from the University of Alabama, Birmingham, found an important missing part of Alzheimer's disease This makes it possible to carry out concept verification experiments with an existing drug that can significantly reduce the pathology and symptoms of Alzheimer's disease in two mouse models, and thus has the potential to provide timely treatment for this devastating disease The relevant research results were published in the Journal of Science Translational Medicine on January 15, 2020 The title of the paper is "β - aminoid redirects norepphine signaling to activate the pathway GSK3 β / tau cascade" Picture from Science Translational Medicine, 2020, DOI: 10.1126/scitranslmed.aay6931 "Our study provides new insights into the potential mechanism of beta amyloid (a β) toxicity, which may have a significant impact on drug design in the future," said Qin Wang, Ph.D., co-author of the paper and researcher at the University of Alabama, Birmingham It identifies the interaction between a β and G protein coupled receptors, which represents an attractive disease-specific therapeutic target for Alzheimer's disease " It is generally believed that the accumulation of a β oligomers in the brain is the inducement to induce the pathological changes of tau protein, which target and kill the neurons in patients with Alzheimer's disease However, the way to connect the two is not clear at present Wang and his colleagues found that a β oligomer hijacks norepinephrine signal in brain neurons, thus wrongly reorienting the signal to activate a kinase called GSK3 β This activated kinase then causes tau protein to be highly phosphorylated, making it toxic to neurons This reorientation of norepinephrine signals occurs on the surface of neurons in a cell membrane receptor called alpha-2a adrenergic receptor (α 2AAR) This receptor is a G protein coupled receptor Wang and his colleagues found that although a certain concentration of a β oligomer can activate GSK3 β, the presence of noradrenaline greatly increased the sensitivity of this activation by two orders of magnitude Therefore, the researchers speculated that the a β oligomer in the human brain at nanomolar concentration could induce the pathogenic GSK3 β / tau cascade reaction in the earliest stage of Alzheimer's disease This theory suggests that many clinical trials to reduce the level of a β oligomers in Alzheimer's patients have failed because they are unable to reduce the level of a β to such a low level α 2AAR usually works by binding noradrenaline, which activates a signal transduction process that mobilizes brain and body action The researchers found that a β oligomer binds to a unique site on α 2AAR, which is different from the binding site of noradrenaline This initiates pathological hijacking This binding at the second site is called allosteric binding In G-protein-coupled receptors, allosteric ligands are known to alter the signal transduction of this receptor, which is a part of normal physiology After the researchers recognized the allosteric binding, they searched to find which kinases might be activated by the binding, which is how they identified GSK3 β Some clinical data support this mechanism The researchers found that α 2AAR from the prefrontal cortex of Alzheimer's patients after death had significantly increased activity compared to the non demented low pathology controls In addition, epidemiological analysis of patients from the national Alzheimer's coordinating center in the United States showed that clonidine, as an α 2AAR activator that can reduce blood pressure, can worsen the cognitive function of patients with cognitive impairment In addition, clonidine has a stronger adverse effect on patients with severe dementia The use of clonidine had no effect on subjects with normal cognitive ability Wang and his colleagues tested an existing drug in a mouse model of Alzheimer's disease: idazoxan Mizolakson is an α 2AAR antagonist, which has been studied in clinical trials of depression One hypothesis is that in the presence of a β pathology, blocking α 2AAR by imidacloprid will show therapeutic potential This was confirmed in the mouse model of Alzheimer's disease At the beginning of 8 months, the mice were treated with imidazolam for 8 weeks At the beginning of the treatment, there were a β plaques in their brains, and α 2AAR showed enhanced activity Compared with the control group, the researchers found that: (1) mizolakson reversed the over activation of GSK3 β in the brains of these mice, further supporting that in vivo, α 2AAR plays a key role in mediating the activation of GSK3 β induced by a β; (2) in the cerebral cortex of the Alzheimer's disease mice model treated by mizolakson, the level of a β load was low, indicating that α 2AA was blocked R slows down the development of a β pathology; (3) mizolakson treatment reduces the density of inflammatory microglia, which indicates the decrease of neuroinflammation; (4) mizolakson treatment can reduce the hyperphosphorylation of tau protein, which indicates that blocking α 2AAR can effectively alleviate the a β induced tau pathology; (5) in two cognitive function tests, the performance of mice treated with mizolakson is almost the same Compared with normal mice, it is better than untreated mice reference material: 1.Fang Zhang et al β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade Science Translational Medicine, 2020, doi:10.1126/scitranslmed.aay6931 2.Pathogenic Alzheimer's disease cascade is activated by faulty norepinephrine signaling