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Excessively reactivated astrocytes explain the unpredictability of Alzheimer’s disease

After hydrogen peroxide and nitric stress, a highly reactive astrocyte is a major indicator of neurodegeneration in Alzheimer’s disease.

Although Alzheimer’s disease (AD) is a common and potentially fatal neurodegenerative disorder of the brain, it appears that most treatments for Alzheimer’s are not making much progress in unraveling the mystery of its cause. Many Alzheimer’s drugs have targeted the elimination of beta-amyloid (Aβ) or amyloid plaques, which block cell-to-cell signals at synapses. But some Alzheimer’s patients continue to show neurodegeneration and cognitive decline even after the amyloid plaques are removed. Conversely, many people do not report any signs of neurodegeneration and cognitive impairment even at very high Aβ. Also, it was never clear why non-neuronal astrocytes, called astrocytes, changed their shapes and functions from the early onset of Alzheimer’s disease and the persistence of this reactive state during the progression of Alzheimer’s.

Researchers at the Center for Cognition and Socialism, within the Institute of Basic Sciences (IBS) and the Korea Institute of Science and Technology (KIST), show that the severity of “ reactive astrocytes ” is a key predictor of the onset of Alzheimer’s disease, which raises the depth. Implications of the current theory of the AD mechanism. In the toxin receptor-based animal model, the research team refined the astrocyte interaction in vivo. They found that reactive light astrocytes can reverse their reaction naturally, while severe reactive astrocytes can cause irreversible neurodegeneration, brain atrophy, and cognitive deficits all within 30 days (Fig.2). Notably, this severe astrocyte reaction induced neurodegeneration has replicated successfully in virus-injected APP / PS1 mice, which have been widely known to lack neurodegeneration. These results indicate that the intense reactive astrocytes are sufficient for neurodegeneration.

“This finding indicates that experiences such as traumatic brain injury, viral infection, and PTSD may be necessary to transform a healthy brain to be susceptible to Alzheimer’s disease through excessive oxidative stress,” says Director C. , The corresponding author of the study. “Excessive oxidative stress disrupts the body’s ability to counteract the harmful effects of excess oxygen-containing molecules, thus converting reactive light astrocytes into highly neurotoxic reactive astrocytes,” explains Dr. Lee. The team revealed that toxin-responsive astrocytes activate a cellular restoration mechanism (or autophagy-mediated lysis pathway) and increase hydrogen peroxide (H2O2) by stimulating monoamine oxidase B (MAO-B). MAO-B plays an important role in reducing dopamine that impedes signal transduction to produce purposeful smooth movement.

This mechanical system results in morphological amplification of astrocyte processes followed by a series of neurodegenerative events: iNOS synthesis enzyme activation, nitric stress, astrocyte activation, and taupathopathy. The research team verified that all Alzheimer’s disease events were suppressed by a recently developed reversible MAO-B inhibitor, KDS2010 or the strong H2O2 scavenger, AAD-2004. This reinforces that the intense reactive astrocytes are the cause of neurodegeneration, not a consequence of it as previously assumed, Director Lee notes. Finally, these molecular features of highly reactive astrocytes are commonly shared in various animal models of Alzheimer’s disease and in the brains of human Alzheimer’s patients.

This study provides plausible explanations for why Alzheimer’s disease is unpredictable: neurodegeneration cannot be reversed by simply activating severe reactive astrocytes. Reactive light astrocytes can be restored unless stretched by other disease burdens. Dr RYU Hoon (at KIST), author of another landscape, says: “It is worth noting that this study indicates that an important step in creating a new treatment strategy for Alzheimer’s disease should be targeting reactive astrocytes that appear to be hyperactive in the early stages of the study. . This should be accompanied by the development of diagnostic tools for reactive astrocytes and early Alzheimer’s disease, adds Dr. Ryo.

Dr CHUN Heejung (at IBS), first author of the study, says, “Reactive astrocytes are a general phenomenon that occurs in many brain diseases such as Parkinson’s disease and brain tumors, as well as Alzheimer’s disease. Based on this study, we have plans to broaden our mechanistic view of neuronal death. Interaction-dependent to include other brain diseases for which a treatment has not yet been developed. ”

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