The reason is cellular "garbage"?
Clearing brain cells of "garbage" saved mice from Alzheimer's disease
American molecular biologists have protected mice from the appearance of Alzheimer's disease with a drug that makes their nerve cells more actively dispose of damaged protein molecules and other cellular "garbage". The results of their study were published by the scientific journal Cell (Bourdenx et al., Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome).
The main sign and possible cause of Alzheimer's disease may be the pathogenic protein beta-amyloid, which accumulates inside brain cells. This protein is a fragment of the APP protein, which plays an important role in the formation of connections between neurons. Another cause of the same disease may be the high concentration of damaged molecules of another substance – tau protein.
Scientists are trying to prevent Alzheimer's disease in two ways: by destroying beta-amyloid plaques, tangles of tau protein and other cellular "garbage" or by preventing them from accumulating inside neurons. However, so far both approaches have not proven their effectiveness in clinical trials.
In a new job, professor of the Medical College named after Einstein's Anna-Maria Cuervo and her colleagues have proposed an alternative way to fight Alzheimer's disease. They took advantage of the already existing "garbage" cleaning systems in the cells, the work of which can be disrupted by neurodegenerative diseases or old age.
Scientists paid special attention to the CMA (chaperone-mediated autophagy) system – a set of protein tags and enzymes that are responsible for detecting and transporting clusters of damaged proteins into lysosomes, cellular "incinerators".
"We knew that the enzymes of the CMA complex are capable of processing damaged tau protein molecules. With the development of Alzheimer's disease, so large amounts of such "garbage" accumulate in cells that this system, in fact, fails. We have created a short molecule that makes cells more actively produce one of the key components of CMA, which normalizes its work," Cuervo explained.
Scientists have tested what happens if you turn off some of its components in the brain cells of mice. It turned out that as a result, tangles of tau protein and beta-amyloid began to form much faster. As a result, rodents were quickly struck by an analog of Alzheimer's disease. However, when scientists increased the activity of CMA, it protected rodents from the death of neurons, even if they were genetically predisposed to develop dementia.
Then Cuervo and her colleagues decided to find out how to increase the activity of CMA without interfering with the patient's genome. To do this, biologists have studied how the work of individual components of this system changes as humans and mice age.
It turned out that the efficiency of its work decreased along with the activity of LAMP2A receptors (variant A of the membrane protein-2 associated with lysosomes, lysosome-associated membrane protein 2) on the surface of lysosomes, which are needed for the transport of protein "garbage" inside these organelles. Guided by this idea, biologists created a small molecule, CA, which restored the normal operation of the LAMP2A gene.
Biologists tested this medicine on two groups of mice that were predisposed to Alzheimer's disease. Further observations showed that the mice who were given CA for several months had improved memory and coordination. This happened even when the rodents received the medicine after the appearance of well-marked symptoms of the disease.
Scientists hope that the medicine they have created will avoid the fate of many other promising remedies for Alzheimer's disease that have not passed the second or third phase of clinical trials. A certain hope for this, according to Cuervo, is given by the fact that the activity of CMA in the cells of both mice and humans decreases in the same way as they age.
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