Experimental drug improves memory
Cellular Cleaning
“Removing 'garbage' from brain cells improves memory in mice,” according to an article in Science Daily about an experimental drug designd by researchers at the Albert Einstein College of Medicine that reversed key symptoms of Alzheimer's disease in mice. The drug’s mechanism of action is to reinvigorate a cellular cleaning mechanism that removes unwanted proteins by digesting and recycling them. The study was published online April 29 in the journal Cell.
Co-study leader Ana Maria Cuervo, M.D., Ph.D., the Robert and Renée Belfer Chair for the Study of Neurodegenerative Diseases, professor of developmental and molecular biology and co-director of the Institute for Aging Research at Einstein, explained, "Discoveries in mice don't always translate to humans, especially in Alzheimer's disease, but we were encouraged to find in our study that the drop-off in cellular cleaning that contributes to Alzheimer's in mice also occurs in people with the disease, suggesting that our drug may also work in humans."
In the 1990s, Dr. Cuervo discovered the existence of this cell-cleaning process, known as chaperone-mediated autophagy (CMA). She has published 200 papers on its role in health and disease. As te Science Daily article explained, CMA gets less efficient as people age, increasing the risk that unwanted proteins can accumulate into insoluble clumps that damage cells. Alzheimer's and all other neurodegenerative diseases are characterized by the presence of toxic protein aggregates in patients' brains. The Cell article described a dynamic interplay between CMA and Alzheimer's disease, with loss of CMA in neurons contributing to Alzheimer's and vice versa. The findings suggested that drugs for bolstering CMA could offer hope for treating neurodegenerative diseases.
To determine whether impaired CMA contributes to Alzheimer's, Dr. Cuervo’s team genetically engineered a mouse to have excitatory brain neurons that lacked CMA. The lack of CMA in one type of brain cell caused short-term memory loss, impaired walking and led to other problems often found in rodent models of Alzheimer's disease. The lack of CMA also profoundly disrupted proteostasis -- the cells' ability to regulate the proteins they contain. Proteins that are usually soluble had shifted to being insoluble and at risk for clumping into toxic aggregates.
Dr. Cuervo also suspected that early Alzheimer's impairs CMA. She and her colleagues studied a mouse model of early Alzheimer's where brain neurons were made to produce defective copies of the protein tau. Evidence shows that abnormal copies of tau clump together to form neurofibrillary tangles that contribute to Alzheimer's. Dr. Cuervo’s team focused on CMA activity within neurons of the hippocampus -- the brain region crucial for memory and learning. CMA activity in those neurons was significantly reduced compared to control animals.
The researchers looked at single-cell RNA-sequencing data from neurons obtained postmortem from the brains of Alzheimer's patients and from a comparison group of healthy individuals to determine whether early Alzheimer's in people blocks CMA too. The sequencing data showed CMA's activity level in patients' brain tissue. CMA activity was somewhat inhibited in people who had been in the early stages of Alzheimer's, followed by much greater CMA inhibition in the brains of people with advanced Alzheimer's.
Dr. Cuervo explained, "By the time people reach the age of 70 or 80, CMA activity has usually decreased by about 30% compared to when they were younger. Most peoples' brains can compensate for this decline. But if you add neurodegenerative disease to the mix, the effect on the normal protein makeup of brain neurons can be devastating. Our study shows that CMA deficiency interacts synergistically with Alzheimer's pathology to greatly accelerate disease progression."
Dr. Cuervo and her team developed a novel drug that shows potential for treating Alzheimer's. "We know that CMA is capable of digesting defective tau and other proteins," said Dr. Cuervo. "But the sheer amount of defective protein in Alzheimer's and other neurodegenerative diseases overwhelms CMA and essentially cripples it. Our drug revitalizes CMA efficiency by boosting levels of a key CMA component."