Closing In On The Cause Of Alzheimer’s Disease

AsianScientist (Dec. 1, 2020) – Despite decades of scientific research, Alzheimer’s disease and its causes still largely remain a mystery. Now, scientists from South Korea have identified a key indicator associated with neurodegeneration in Alzheimer’s. Their findings was published in Nature Neuroscience.

Poignantly depicted in Hollywood films like The Notebook and Still Alice, Alzheimer’s disease is a brain disorder that accounts for a majority of cases of dementia, the progressive loss of memory and other cognitive abilities. Over the years, numerous hypotheses regarding the cause of Alzheimer’s have been presented.

Perhaps the most prominent is the amyloid hypothesis, which pins the progression of Alzheimer’s on the build-up of beta-amyloid (Aβ) plaques in the brain. These plaques block cell signalling—potentially triggering inflammation and leading to brain cell death.

Interestingly, studies have shown that some Alzheimer’s patients continue to display neurodegeneration even after the removal of Aβ plaques. Even stranger, other people show no signs of cognitive impairment despite having high levels of Aβ. These seemingly contradictory results suggest that there are other factors at play for the disease.

Using a new animal model, researchers from the Institute for Basic Science and Korea Institute of Science and Technology have shown that star-shaped brain cells called astrocytes may be the key to understanding Alzheimer’s unpredictability.

Neurodegeneration typically leads to an abnormal increase in the size and number of astrocytes. In this study, the team discovered that the degree of astrocyte reactivity was linked to Alzheimer’s progression.

They did this by crossing two mouse lines: one expressing diphtheria toxin-sensitive receptors and another that localized the expression of these receptors to astrocytes. By controlling the amount of diphtheria given to the new mouse model, the researchers were able to fine-tune astrocyte reactivity and replicate the conditions observed in Alzheimer’s patients.

In the process, they found that astrocytes with a mild degree of abnormal growth could naturally reverse their reactivity. On the other hand, severely reactive astrocytes could cause permanent neurodegeneration and cognitive impairments within 30 days.

The team also showed that mildly reactive astrocytes could be transformed into their severe, neurotoxic counterparts after overexposure to oxygen-containing molecules, or oxidative stress. Accordingly, blocking these molecules slowed down astrocyte reactivity.

In sum, the team’s study provides a plausible explanation for why patients with advanced Alzheimer’s can display continued symptoms even after the removal of Aβ plaques. Once severe reactive astrocytes are present, neurodegeneration is irreversibly set into motion regardless of the presence or absence of Aβ plaques. At the same time, their research accounts for why many individuals lack neurodegeneration and cognitive impairment even with a high Aβ burden.

“Notably, this study suggests that an important step to establishing a new treatment strategy for Alzheimer’s disease should be targeting reactive astrocytes that appear to be overly activated in the early stages,” concluded corresponding author Dr. Ryu Hoon. “This should be accompanied by the development of the diagnostic tools for reactive astrocytes and early Alzheimer’s disease.”

The article can be found at: Chun et al. (2020) Severe Reactive Astrocytes Precipitate Pathological Hallmarks of Alzheimer’s Disease via H₂O₂− production.

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Source: Institute for Basic Science; Photo: Shutterstock.
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