Cell: Enhance neuronal autophagy, clear brain toxic proteins, reverse Alzheimer's disease, and anti-aging

Alzheimer's disease (AD), commonly known as "Alzheimer's disease", is a serious neurodegenerative disease.

Currently, about 50 million people worldwide suffer from Alzheimer's disease.

On April 22, 2021, researchers from the Albert Einstein College of Medicine in the United States published a research paper titled: Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome in the Cell journal.

The research team has developed an experimental drug that can clear the tau protein by activating chaperone-mediated autophagy (CMA) in brain neurons and reverse key symptoms in a mouse model of Alzheimer's disease.

In the 1990s, Dr.

As we age, the efficiency of chaperone-mediated autophagy (CMA) will decrease, causing harmful proteins to accumulate into insoluble clumps, risking cell damage.

In fact, the common feature of Alzheimer's disease and all other neurodegenerative diseases is the presence of toxic protein aggregates in the patient's brain.

The research of this Cell paper led by Dr.

build connection

The research team first investigated whether the impairment of molecular chaperone-mediated autophagy (CMA) contributes to Alzheimer's disease.

To this end, the research team genetically modified the mice to have excitatory brain neurons that lack CMA.

Dr.

The research team studied a mouse model of early Alzheimer’s disease.

Then, the research team focused on observing the CMA activity in the hippocampal neurons of the mouse model, which are essential for memory and learning.

So what happened in the brains of early Alzheimer's patients? Does it block chaperone-mediated autophagy (CMA)?

In order to find these answers, the research team compared the single-cell RNA sequencing data of brain neurons of Alzheimer's patients and healthy people's brain neurons, confirming that the CMA activity in the brain neurons of early Alzheimer's patients has received a certain degree.

According to Dr.

The above studies have shown that the decreased activity of molecular chaperone-mediated autophagy (CMA) interacts with the pathology of Alzheimer's disease, and through synergy, greatly promotes the development of the disease.

Turn things around

In chaperone-mediated autophagy (CMA), the chaperone protein binds to damaged or defective proteins in the cell, and the chaperone transports it to the lysosome of the cell for digestion and waste recovery.
In order to successfully transport it into the lysosome, the chaperone protein must first "docking" it on the LAMP2A protein receptor, which is located on the surface of the lysosome.

Chaperone-mediated autophagy (CMA) can digest defective tau protein and other proteins, but patients with Alzheimer's disease and other neurodegenerative diseases have decreased CMA efficiency, and too much tau protein makes them overwhelmed.

Therefore, the research team developed a new drug called CA that can increase the level of LAMP2A receptors on the lysosome.
The more LAMP2A receptors on the lysosome, the higher the level of CMA activity.

The research team tested CA drugs in a mouse model of Alzheimer's disease and found that oral CA for more than 4 to 6 months can improve memory, improve depression and anxiety symptoms, and improve exercise capacity.
And the levels of tau protein and protein clumps in the brains of Alzheimer's mice after treatment were significantly reduced.

Compared with mice with Alzheimer's disease that were not treated with the drug (left), mice treated with the drug (right) had fewer toxic protein clumps in the brain

Accelerate commercialization

Importantly, these Alzheimer's mice have shown symptoms of the disease, and their neurons were blocked by toxic protein clumps before the administration.
The treatment results show that the drug can help maintain and restore neuronal function even in the late stage of Alzheimer's disease, and the drug can also significantly reduce glial degeneration.
And taking it for a long time, no side effects on other organs were found.

On January 13, 2021, Dr.
Ana Maria Cuervo published a paper in Nature and found that molecular chaperone-mediated autophagy (CMA) can maintain the function of hematopoietic stem cells.
Therefore, CMA has the potential to enhance the function of hematopoietic stem cells under aging or stem cell transplantation.
Target.

We all know that drugs that are effective in mice are not necessarily effective in humans.
However, this study found that the efficiency of molecular chaperone-mediated autophagy (CMA) that causes Alzheimer’s disease in mice also decreases, which also occurs in Alzheimer’s disease.
Among patients with Zheimer's disease.
This indicates that the drug developed by the research team is likely to be effective for the human body.

Dr.
Ana Maria Cuervo

Dr.
Ana Maria Cuervo and Dr.
Evripidis Gavathiotis, in cooperation with Life Biosciences, established Selphagy Therapeutics.
The company is currently developing the drug named CA and its related compounds in the paper for the treatment of Alzheimer’s disease and other Neurodegenerative diseases.

Original source:

Mathieu Bourdenx, et al.
Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome.
Cell, April 22, 2021 DOI: https://doi.
org/10.
1016/j.
cell.
2021.
03.
048.