Alzheimer's disease is a neurodegenerative disease with insidious onset and progressive development, of which the clinical features are mainly cognitive impairment, abnormal mental behavior, and decline in social life function. Generally, early onset usually occurs before the age of 65. A family tendency is called familial Alzheimer's disease, and no family tendency is called sporadic Alzheimer's disease.

According to the WHO, about 50 million people worldwide suffer from dementia, of which Alzheimer's disease is the most common type. Possible risk factors for Alzheimer's disease include increasing age, gender, low education level, smoking, middle-aged hypertension and obesity, hearing impairment, brain trauma, lack of exercise, social loneliness, diabetes, and depression.

In a latest study, researchers from the Albert Einstein School of Medicine designed an experimental drug that can reverse the key symptoms of Alzheimer's disease in mice models ( The drug works by reactivating a protein that is not needed for digestion and recycling to remove their cell cleansing mechanism. The relevant research results were published online in Cell on April 22, 2021, entitled "Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome".

The researchers said that the findings made in mice are not always applicable to humans, especially in Alzheimer's disease, but they found that the decrease in cell cleaning ability that leads to Alzheimer’s disease mouse models also occurred in patients, suggesting that the drug may also work in humans.

In the 1990s, Dr. Ana Maria Cuervo, co-director of the Institute of Aging at the Albert Einstein School of Medicine, discovered this cell cleansing process called chaperone-mediated autophagy (CMA). So far, 200 papers have been published on its role in health and disease.

As people age, the efficiency of CMA declines, which increases the risk of unwanted proteins accumulating into insoluble clumps that damage cells. In fact, Alzheimer's disease and all other neurodegenerative diseases are characterized by the presence of toxic protein aggregates in the patient's brain. In this study, those researchers revealed the dynamic interaction between CMA and Alzheimer's disease that the loss of CMA in neurons can promote Alzheimer's disease and vice versa. These findings indicate that drugs that activate CMA may be hopeful for the treatment of neurodegenerative diseases.

The researchers first studied whether damage to CMA can cause Alzheimer's disease. To this end, they genetically modified mice to have excitatory brain neurons that lack CMA. The lack of CMA in brain cells is sufficient to cause short-term memory loss, walking impairment, and other problems often found in rodent models of AD. In addition, the lack of CMA greatly disrupts proteostasis, the ability of cells to regulate the proteins they contain. Under normal circumstances, soluble proteins have become insoluble, and there is a risk of forming toxic aggregates.

Researchers speculate that the reverse is also true that early AD can damage CMA. Therefore, they studied a mouse model of early AD, in which brain neurons were modified to produce defective versions of the tau protein. There is evidence that abnormal versions of tau protein clump together to form neurofibrillary tangles, which can lead to AD. They focused on the CMA activity in neurons in the hippocampus, a brain area that is essential for memory and learning. They found that in this mouse model, the CMA activity in these neurons was significantly reduced compared to the control group.

One of the encouraging findings is that researchers have developed a new type of drug that has shown the potential to treat AD, which re-enhances the efficiency of CMA by increasing the level of a key CMA component.

In CMA, proteins called chaperones bind to damaged or defective proteins in cells. Molecular chaperones transport the complex to the lysosome of the cell, a membrane organelle that contains enzymes which digest and recycle waste. The chaperones must first "dock" the complex to a protein receptor called LAMP2A that grows from the membrane of the lysosome. The more LAMP2A receptors on the lysosome, the higher the level of potential CMA activity. This new drug called CA works by increasing the number of such LAMP2A receptors, which restores LAMP2A to youthful levels, allowing CMA to remove defective tau and other defective proteins so that they cannot form toxic protein clumps.

Researchers tested CA in two different mouse model types, showing that oral doses of CA given over a period of 4 to 6 months can improve memory and reduce depression and anxiety. The walking ability was significantly improved in the other group. And in the brain neurons of the two model types, the drug significantly reduced the levels of tau protein and protein clumps compared to untreated mice.

Importantly, both models had AD symptoms, whose neurons had been blocked by toxic proteins before the medication. It means that the drug may help protect neuronal function, even in the later stages of the disease. Another encouraging finding was that the drug significantly reduces gliosis, the inflammation and scar formation of cells surrounding neurons in the brain. Glial hyperplasia is related to toxic proteins and is known to play an important role in perpetuating and exacerbating neurodegenerative diseases.

Treatment with CA does not seem to damage other organs, even when administered daily for a longer period. Researchers are currently developing CA and related compounds for the treatment of Alzheimer's disease and other neurodegenerative diseases.

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