Alzheimer's disease: brain defense mechanism discovered

Scientists from UCLA Health and UC San Francisco have identified the cause of the accumulation of a harmful protein in some brain cells. It is these cells that trigger Alzheimer's disease. The toxic protein is called tau protein. The findings explain why some neurons live longer.

The study was based on an advanced genetic screening technique using CRISPR in laboratory-grown human neurons, writes xrust. The goal was to map the internal systems that control the accumulation of tau protein in brain cells.

When tau protein clumps, it damages and eventually kills neurons, contributing to the development of diseases such as frontotemporal dementia and Alzheimer's disease. Tau protein is the most common protein known to aggregate in neurodegenerative diseases, but scientists have long puzzled over why some neurons are more vulnerable than others.

CRISPR screen reveals Tau protein clearance system

The results suggest that activating this natural clearance mechanism could form the basis of new therapies for neurodegenerative diseases that affect millions of Americans and for which there are still no effective treatments.

In experiments using neurons derived from human stem cells, the researchers turned off individual genes to see how each affected the accumulation of toxic tau protein. Of the more than 1,000 genes identified during the screen, the CRL5SOCS4 gene stood out among the others. It works by attaching chemical markers to the tau protein, signaling the cell's recycling machinery to destroy it.

In a study of brain tissue from people with Alzheimer's disease, researchers found that neurons with higher levels of CRL5SOCS4 components were more likely to survive despite the accumulation of tau protein.

Mitochondrial stress and harmful fragment of the Tau protein

class=»notranslate»>__GTAG5__ The study also revealed an unexpected link between mitochondrial problems and tau protein toxicity. Mitochondria serve as energy generators in the cell. When the researchers disrupted these energy-producing structures, the cells began producing a specific fragment of tau protein that was about 25 kilodaltons in size. This fragment is very close to a biomarker found in the blood and cerebrospinal fluid of Alzheimer's patients known as NTA-tau.

This fragment of tau protein appears to be formed when cells are exposed to oxidative stress, which is common in aging and neurodegenerative diseases, the scientists said. They found that this stress reduces the efficiency of the proteasome, the cell's protein processing system, causing it to improperly process tau protein.

Laboratory experiments have shown that this altered fragment of tau protein changes the way tau proteins cluster, which may influence disease progression.

Output

The findings open up several potential therapeutic avenues. Increasing CRL5SOCS4 activity may help neurons remove tau protein more efficiently. At the same time, protecting the proteasome during periods of cellular stress can reduce the formation of harmful tau protein fragments.

Xrust Alzheimer's disease: brain protective mechanism discovered