Alzheimer's Experimental New Drug Starts Commercialization


Chaperone-mediated autophagy (CMA) in neurons. A protein protector (red circle) that escorts the damaged tau protein (green) molecule docks to the LAMP2 receptor (blue) in the cell's lysosome (orange) and pushes the tau protein inside the lysosome to break it down. © Albert Einstein College of Medicine
Chaperone-mediated autophagy (CMA) in neurons. A protein protector (red circle) that escorts the damaged tau protein (green) molecule docks to the LAMP2 receptor (blue) in the cell's lysosome (orange) and pushes the tau protein inside the lysosome to break it down. © Albert Einstein College of Medicine

A research team from Albert Einstein Medical School in the United States developed an experimental drug that reverses the main symptoms of Alzheimer's disease in a study using mice. The drug works by activating a cellular washing mechanism that breaks down or recycles and removes unwanted proteins.


The research team published this research on the 22nd of the biotechnology journal cell and established a pharmaceutical company for commercialization and is currently developing new drugs.


Dr. Ana Maria Cuervo, Professor of Development and Molecular Biology at Albert Einstein University and Chair of the Neurodegenerative Diseases Research Group, who led the study, said, However, this study suggests that this drug may also work in the human body, as the decline in cell washing involved in Alzheimer's disease occurs in Alzheimer's patients.


Dr. Cuervo discovered in the 1990s a process of cell purification known as chaperone-mediated autophagy (CMA) and published 200 papers on how this process plays a role in health and disease. Have been announced.


It is known that CMA becomes less efficient with aging, increasing the risk of unwanted proteins accumulating into insoluble masses that damage cells. In fact, Alzheimer's disease and all other neurodegenerative diseases are characterized by toxic protein aggregates found in the patient's brain.


This study shows that CMA loss in neurons contributes to the development of Alzheimer's and vice versa, indicating a dynamic interaction between CMA and Alzheimer's disease.


Establishing the link between CMA and Alzheimer's disease


Dr. Cuervo's team first investigated whether impaired CMA contributes to the development of Alzheimer's disease. To do this, the researchers manipulated the gene in the mice to remove CMA from excitable brain neurons.


The absence of CMA in some types of brain cells leads to short-term memory loss, gait impairment, and several problems often found in rodent models with Alzheimer's disease.


In addition, the absence of CMA severely impairs protein homeostasis, the ability of cells to regulate proteins. This increases the risk of toxic aggregates by turning the protein that is normally soluble into insoluble.


Dr. Cuervo also questioned the opposite case: whether early Alzheimer's disease inversely damages CMA. Under these doubts, the team studied a mouse model of early Alzheimer's disease that was engineered to produce a defective tau protein.


Research has revealed evidence that abnormal copies of the tau protein aggregate together to form nerve fiber tangles that can lead to Alzheimer's disease.


Focusing on CMA activity in neurons in the hippocampus, an area of ​​the brain important for memory and learning, the researchers found that this CMA activity was significantly reduced compared to control animals.


Alzheimer's patients significantly inhibited CMA activity


So, will CMA activity be blocked even in people with early Alzheimer's disease?


To confirm this, the researchers examined single-cell RNA sequencing data from the brains of Alzheimer's patients and neurons obtained post-mortem of a healthy comparison group. Sequencing data reveals the level of CMA activity in brain tissue.


Certainly, CMA activity was somewhat suppressed in people in the early stages of Alzheimer's disease, and CMA activity was significantly suppressed in the brains of patients with advanced Alzheimer's disease.


Dr. Cuervo said, when people reach the age of 70-80, CMA activity decreases by about 30% compared to when they were young. Most people's brains can compensate for this reduction, but when neurodegenerative diseases are mixed, It can have a devastating effect on the normal protein composition of neurons. The study shows that CMA deficiency has a synergistic effect with Alzheimer's pathology and significantly accelerates disease progression.


A comparison of a rat model with Alzheimer's disease treated with CA drugs (right) versus untreated. Brain neurons from drug-treated mice contain significantly less toxic protein masses than untreated mice. © Albert Einstein College of Medicine
A comparison of a rat model with Alzheimer's disease treated with CA drugs (right) versus untreated. Brain neurons from drug-treated mice contain significantly less toxic protein masses than untreated mice. © Albert Einstein College of Medicine

New drug cleans neurons and reverses symptoms


With these encouraging discoveries, Dr. Cuervo's team has developed a new drug that demonstrates the potential to treat Alzheimer's disease.


Dr. Cuervo said, CMA can break down defective tau and other proteins. However, because the amount of defective proteins contained in Alzheimer's and other neurodegenerative diseases overwhelms CMA, it essentially causes disability. The drug we developed has boosted the level of CMA's key ingredients to revive the effectiveness of CMA.


Proteins called chaperones in CMA bind to damaged or defective proteins in body cells. Guardians transport this cargo to the cell's lysosomes (membrane-bound small organelles filled with enzymes) to break down and recycle waste.


However, in order to successfully bring the cargo to the lysosome, the guardian must first dock to a substance in the protein receptor called LAMP2A that comes out of the lysosome's membrane.


The more LAMP2A receptors in the lysosome, the higher the likelihood of CMA activity. A new drug called CA acts to increase the number of LAMP2A receptors.


Dr. Cuervo said, a person produces the same amount of LAMP2A receptors throughout their lifetime. Because these receptors weaken quickly with age, the receptors that deliver unwanted proteins to the lysosome tend to decrease.


The new drug CA restores receptor LAMP2A to youthful levels, preventing CMA from removing tau and other defective proteins from forming toxic protein masses.


Dr. Cuervo's team reported in Nature Communications this month that for the first time, lysosomes are isolated from the brains of Alzheimer's disease patients, and when the number of LAMP2A receptors decreases, CMA is lost in humans as in the Alzheimer's animal model.

Ana Maria Cuervo, a professor at Albert Einstein University in the U.S., is developing new drugs by jointly researching Alzheimer's disease treatment, establishing a pharmaceutical venture and developing new drugs. © Albert Einstein College of Medicine
Ana Maria Cuervo, a professor at Albert Einstein University in the U.S., is developing new drugs by jointly researching Alzheimer's disease treatment, establishing a pharmaceutical venture and developing new drugs. © Albert Einstein College of Medicine

Venture pharmaceutical companies to established for Alzheimer's drug development


The researchers tested the new drug CA in two mouse models. When CA was administered orally to two disease model mice over 4-6 months, memory, depression, and anxiety were improved, and it was found to be almost similar to that of the healthy control group.


Mice with gait impairment significantly improved their gait ability, and the levels of tau protein and protein mass were significantly reduced in the two models of brain neurons compared to the control group that did not receive the drug.


Dr. Cuervo said, the two animal models already showed disease symptoms at the time of the experiment, and nerve cells were clogged with toxic proteins before drug administration. It means that it can be helpful. We are also very excited to know that this drug has greatly reduced gliosis, which causes inflammation and scratches in the cells surrounding the nerve cells in the brain. It is known to play an important role in continuing and exacerbating brain diseases.


The CA drug is a new drug designed by biochemistry professor Evripidis Gavathiotis, who led the study and was shown to be harmless to other body organs even if administered daily for a long period of time.


Cuervo and Professor Gabarthiotis collaborated with Boston-based Life Biosciences to create Selphagy Therapeutics, which is now developing compounds for the treatment of Alzheimer's disease and other neurodegenerative diseases have.

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