Alzheimer’s: A study published in the journal Cell, on April 22, brings hope for people with Alzheimer’s: an experimental drug can increase the quality of life and restore autonomy for people affected by the disease. The discovery was made by the team of post-doctoral researcher Ana Maria Cuervo, a specialist in neurodegenerative diseases at the Albert Einstein College of Medicine, in New York, in the United States.
The experimental drug has been shown to reverse the main symptoms of the disease in mice. The drug works by reinvigorating a cell cleaning mechanism that eliminates unwanted proteins, digesting and recycling them. The research leader cautioned, however, that the findings in mice do not always translate into humans, especially Alzheimer’s disease.
Despite the doubt, Cuervo told Science Daily that the drop in cell cleansing that contributes to Alzheimer’s disease in mice also occurs in people with the disease. “This suggests that our drug may also work in humans,” she said.
Cellular cleaning and Alzheimer’s
In the 1990s, Dr. Cuervo discovered the existence of a cell cleaning process: Autophagy Mediated by Chaperones (CMA). Since then, she has published 200 articles on the role of the process in human health and Alzheimer’s disease.
CMA becomes less efficient as people age, increasing the risk that unwanted proteins will accumulate in insoluble clusters that damage cells. All neurodegenerative diseases – including Alzheimer’s – are characterized by the presence of toxic protein clusters in patients’ brains.
The article published in Cell reveals a dynamic interaction between CMA and Alzheimer’s – with the loss of CMA contributing to Alzheimer’s and vice versa. The findings suggest that drugs that accelerate CMA may offer hope for the treatment of neurodegenerative diseases.
How the study was done
The research team first looked at whether the decrease in CMA contributed to Alzheimer’s, creating a mouse with brain excitatory neurons without CMA. The absence of the mechanism caused short-term memory loss, limited mobility and other problems frequently encountered in rodents with the disease.
The researchers realized that the absence of CMA disrupts proteostasis – the cells’ ability to regulate their proteins. Without it, normally soluble proteins become insoluble, therefore, with the risk of assembling in toxic clusters.
Dr. Cuervo suspected that the reverse was also true: early Alzheimer’s would harm CMA. So she and her colleagues studied an early-stage Alzheimer’s mouse that produced defective copies of the tau protein – evidence indicated that abnormal copies of tau clustered together to form neurofibrillary tangles that contribute to Alzheimer’s.
The team focused on cell cleaning within the neurons of the hippocampus – a brain region crucial for memory and learning – and found that, in these neurons, CMA activity was significantly reduced compared to healthy animals.
Alzheimer’s in humans
The researchers found that early Alzheimer’s in humans also blocks CMA, analyzing the RNA sequencing of brain neurons in healthy patients who also have the disease at different stages.
“When people are between 70 and 80, CMA activity generally decreases by about 30% compared to when they were younger,” said the scientist. “Most people’s brains can compensate for this decline. But if you add neurodegenerative diseases to the mix, the effect on the normal protein composition of brain neurons can be devastating,” she explained.
New Alzheimer’s Drug
The team developed a drug that revitalizes CMA’s efficiency by increasing the levels of a key component of the cell cleaning process: the LAMP2A protein receptor. The more LAMP2A receptors in cells, the higher the level of CMA activity. The new drug, called CA, increases the number of these receptors.
In all mice, oral doses of CA administered for four to six months led to improvements in memory, depression and anxiety. The ability to move around has also improved. In brain neurons, the drug significantly reduced levels of tau protein and toxic protein clusters compared to untreated animals. CA treatment did not appear to harm other organs, even when administered daily for long periods.