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The study, published today in the journal 'Cell', has been directed by one of the most prominent scientists in Spain, Ana María Cuervo, doctor of the Robert and Renée Belfer Chair for the Study of Neurodegenerative Diseases at Albert Einstein College. of Medicine of New York.
Researchers at the Albert Einstein College of Medicine in New York have designed an experimental drug that enhances a type of autophagy, a natural cellular cleaning mechanism that eliminates unwanted proteins and is capable of reversing the symptoms of Alzheimer's disease in mice. , the previous step for it to work in humans.
The study, published this Thursday in the journal 'Cell', has been directed by one of the most prominent scientists in Spain, Ana María Cuervo, doctor of the Robert and Renée Belfer Chair for the Study of Neurodegenerative Diseases and co-director of the Institute. of Research on Aging at the Albert Einstein College of Medicine in New York.
"Discoveries in mice do not always translate to humans, especially in Alzheimer's disease," and "we do not want to create false expectations," warns Cuervo, but, with this research, "we think it could work because all we are doing is restore cell function to a youthful level," explains the doctor. To do this, "we basically use the natural way cells eliminate toxicity in a young person," she insists.
The compound reactivates chaperone-mediated autophagy (CMA), a cellular cleansing process key to health and aging, discovered by this cell biologist in the 90s. As we age, autophagy loses efficiency and allows toxic proteins to escape. accumulate causing damage to cells. It's like putting the garbage in bags and not having the garbage man take them away; When this occurs, the brain develops neurodegenerative diseases such as Alzheimer's, whose patients have toxic protein aggregates in the brain, like garbage bags on a cleaning strike.
In this work, Dr. Cuervo demonstrates that the loss of AMC in neurons contributes to the development of Alzheimer's in animals and vice versa, that in Alzheimer's models the AMC is decreased, which means that drugs to reactivate this form of autophagy could treat neurodegenerative diseases.
First, Cuervo and his team analyzed whether the alteration of the AMC contributes to Alzheimer's, and to do so they used a genetically modified mouse in which the excitatory brain neurons lacked this cellular cleaning process.
This lack of AMC caused short-term memory loss, movement difficulties and other problems related to the symptoms of Alzheimer's disease but, above all, it profoundly altered proteostasis, that is, the ability of cells to regulate and degrade proteins. proteins they contain.
Cuervo suspected that the opposite was also true and that early Alzheimer's affected the AMC, so he studied a mouse model of early Alzheimer's in which the neurons produced defective copies of the tau protein (key in the development of the disease).
Then, using patients, they observed that the level of AMC activity in brain tissue was somewhat inhibited in the early stages of Alzheimer's, and much more inhibited in cases of patients with advanced Alzheimer's.
When people reach 70 or 80 years of age, AMC activity is usually around 30% decreased, a reduction in activity that the brain of most people can compensate for but which, if it coincides with a neurodegenerative disease , becomes a mixture with devastating effects.
These investigations have been the basis of the drug developed by Cuervo, a compound that improves AMC by raising the levels of a key component: the LAMP2A receptor, which receives damaged proteins attached to chaperones to destroy them in lysosomes (the 'clean spots'). ' in which cellular debris is removed).
This compound, called CA, restores LAMP2A to youthful levels and helps AMC get rid of tau and other defective proteins so they don't form toxic clumps. The drug, given to two different mouse models of Alzheimer's disease for 4 to 6 months, improved memory, depression, anxiety and motor ability without harming other organs.
"The drug does not attack the cause of Alzheimer's, but the consequence, which is the accumulation of toxic proteins inside the cell, which causes the symptoms. Therefore, if it works, we hope to be able to keep patients asymptomatic, like when they were 20 years old. "Details the doctor.
This will require studies with other animals more similar to humans (to ensure that it does not have toxic effects), while Cuervo and his team continue to look for alternative mechanisms to stimulate cellular cleaning and see if they can be used in other diseases.
