The real culprit of Alzheimer's disease may have been found, new study answers two core questions

The study presents a disease-causing model of beta amyloid (Photo: References)In Alzheimer's patients, scientists observed a large amount of beta amyloid depositionIn the past, the prevailing view was that the accumulation of these proteins was the cause of the disease, and many pharmaceutical companies have developed a variety of drugs that target these protein depositsAlthough these drugs can effectively block the formation of protein deposits, they have encountered Waterloo in clinical trials, unable to slow the progression of the diseaseThis has also led academics to question the "beta amyloid" theory, that it is wrongother scientists feel that clinical trials have failed because we still don't know exactly how beta amyloid worksIn an op-ed on Science, the authors point out that we do not yet know what form of beta amyloid protein is neurotoxic in neurons ( monomers , oligomers , or polysacchaes )In addition, we do not know how these proteins affect nerve functionthe journal Science, which has a high opinion on the study and has made a special review (Photo source: References)in this paper, the researchers answered both questionsIn recent studies, it has been found that Alzheimer's disease, while a "degenerative disease", is "overactive" in neurons in the early stagesTo reveal the mechanism behind it, the scientists used dual photon imaging to quantitatively analyze neurons in the hippocampusThey found that the introduction of a mutated beta amyloid bipolymer (A beta S26C)2, as long as neurons had underlying activity, triggered hyperactivity of neuronsThis finding has been confirmed in both in vivo and in vitro experimentsin basically active neurons, the mutant beta amyloid dimine causes neurons to become hyperactive (Photo Source: References1)and then they begin to study why these neurons become hyperactive under the action of beta amyloid dipolionsPast literature has suggested that this abnormality in neurons may be related to the steady state of glutamate To do this, the researchers tried a glutamate reabsorption inhibitor to simulate the effects of beta amyloid bipolymers And the animal research results are exactly as they expected! In wild mice, both pathogenic proteins and drugs that inhibit glutamate absorption can induce excessive neuronal activation Backed by other research data, the team points out that there are similar mechanisms behind these two approaches , beta amyloid bipolymers cause overactivation of neurons, which are associated with abnormal lyucine reabsorption brain extracts from human patients can also cause similar overactivity (Photo: References) to confirm that their findings are clinically demeaning, the researchers tested brain tissue extracts from Alzheimer's patients Studies have shown that these extracts from real patients can also stimulate hyperactivity of neurons The results of biochemical analysis also pointed out that the beta amyloid protein mainly is a monopolymer and a stable bipolymer under experimental conditions And if these beta amyloid proteins are removed by immune means, extracts of brain tissue cannot activate the overactivity of neurons These results again demonstrate the effect of beta amyloid on abnormal neuronal activation based on these findings, the researchers came up with a model of Alzheimer's disease They point out that a small amount of beta amyloid prevents glutamate from reabsorption in the brain region, causing glutamate to accumulate around synapses This accumulation promotes depolarization, which further activates neurons and creates a vicious circle a graphic illustration of the study (Photo: References; author Kelly Holoski) a review of these findings in an op-ed in the journal Science Past mouse studies have shown that there is a lot of glutamate near amyloid deposition, and that glutamate transport receptors can also be defective in human patients, the paper said The findings of this paper are consistent with these evidences these findings are also important for the treatment of Alzheimer's disease, and it is a good explanation for why many drugs have failed miserably in clinical trials - most of them are used when patients "have mild symptoms" - but this is the end of the disease Although they effectively remove the deposition of beta amyloid protein, they do not help inhibit the soluble beta amyloid monomer or bipolymer According to this study, these may be the key to disease They were already disrupting the function of neurons long before symptoms appeared to do this, the researchers say, we need to better understand how these beta amyloid proteins interfere with the reabsorption of glutamate and whether they have a direct inhibition or indirect interference effect In addition, glutamate antagonists, or drugs that promote glutamate transport protein function, may alleviate the condition The treatment of reducing beta amyloid oligomers, rather than sedimentation, may be an important research direction in the future References: S Benedikt Zott et al., (2019), A vicious cycle of beta amyloid-dependent neuronal hyperactivation, Science, DOI: 10.1126/science.aay0198 , Dennis J Selkoe, (2019), Early dysfunction network in Alzheimer's, Science, DOI: 10.1126/science.aay5188
Original title: This Science paper published today may have found the key to the treatment of Alzheimer's disease