Researchers at Albert Einstein College of Medicine have designed an experimental drug that reversed key symptoms of Alzheimer’s disease in mice. The drug works by reinvigorating a cellular cleaning mechanism—chaperone-mediated autophagy (CMA)—that gets rid of unwanted proteins by digesting and recycling them. “Discoveries in mice don’t always translate to humans, especially in Alzheimer’s disease,” said co-study leader Ana Maria Cuervo, MD, PhD, 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. “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.”
The results reveal a dynamic interplay between CMA and Alzheimer’s disease, with loss of CMA in neurons contributing to Alzheimer’s, and vice versa. The findings suggest that drugs for revving up CMA may offer hope for treating neurodegenerative diseases.
Cuervo and colleagues report on their work in Cell, in a paper titled, “Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome.”
All cells rely on intracellular surveillance systems to maintain proteome’s homeostasis, or proteostasis—the cells’ ability to regulate the proteins they contain—and age-related deficits in protein quality control in neurons can increase the risk of neurodegenerative diseases, the authors wrote.
In CMA, proteins called chaperones bind to damaged or defective proteins in cells of the body. The chaperones ferry their cargo to the cells’ lysosomes—membrane-bound organelles filled with enzymes—which digest and recycle waste material. However, CMA becomes less efficient as people age, increasing the risk that unwanted proteins will accumulate into insoluble clumps that damage cells. Cuervo discovered the existence of CMA in the 1990, and has published 200 papers on its role in health and disease.
Alzheimer’s disease and all other neurodegenerative diseases are characterized by the presence of toxic protein aggregates in patients’ brains. “In fact, the presence of protein aggregates is a common feature in neurodegenerative patient brains,” the authors noted. And even in the absence of neurodegenerative disease, most elderly brains display some protein aggregation.
For their reported studies, Cuervo and colleagues turned to rodent models to first investigate whether impaired CMA contributes to Alzheimer’s disease. They genetically engineered a mouse to have excitatory brain neurons that lacked CMA. The absence of CMA in one type of brain cell was enough to cause short-term memory loss, impaired walking, and other problems often found in rodent models of Alzheimer’s disease. In addition, the absence of CMA profoundly disrupted proteostasis. Proteins that were usually soluble had become insoluble and at risk for clumping into toxic aggregates.
Cuervo suspected that the converse was also true, and that early Alzheimer’s disease might impair CMA. So the team then looked at a mouse model of early Alzheimer’s disease in which brain neurons were made to produce defective copies of the protein tau. (Evidence indicates that abnormal copies of tau clump together to form neurofibrillary tangles that contribute to Alzheimer’s disease.) The researchers focused on CMA activity within neurons of the hippocampus, the brain region that is crucial for memory and learning. They found that CMA activity in those neurons was significantly reduced in the Alzheimer’s disease mice, compared with activity in the same neurons in control animals.
To investigate whether early Alzheimer’s disease might block CMA in humans, the researchers then looked at single-cell RNA-sequencing data from neurons obtained postmortem from the brains of Alzheimer’s disease patients, and from a comparison group of healthy individuals. The sequencing data revealed the level of CMA activity patients’ brain tissue, and showed that while CMA activity was somewhat inhibited in the neurons of people who had been in the early stages of Alzheimer’s, there was much greater CMA inhibition in the brains of people with advanced Alzheimer’s.
“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,” said Cuervo. “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.”
Cuervo and her team have developed a novel drug that shows potential for treating Alzheimer’s disease. “We know that CMA is capable of digesting defective tau and other proteins,” said 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.”
In CMA, proteins called chaperones bind to damaged or defective proteins in cells of the body. The chaperones ferry their cargo to the cells’ lysosomes—membrane-bound organelles filled with enzymes—which digest and recycle waste material. To successfully get their cargo into protein-digesting lysosomes, chaperones must first “dock” the material onto a membrane-bound protein receptor called LAMP2A (lysosome-associated membrane protein type 2A; L2A). The more LAMP2A receptors there are on lysosomes, the greater the level of CMA activity that is possible. The new drug, called CA, works by increasing the number of those LAMP2A receptors. The drug was designed by co-study lead Evripidis Gavathiotis, PhD, professor of biochemistry and of medicine.
“You produce the same amount of LAMP2A receptors throughout life,” Cuervo explained. “But those receptors deteriorate more quickly as you age, so older people tend to have less of them available for delivering unwanted proteins into lysosomes. CA restores LAMP2A to youthful levels, enabling CMA to get rid of tau and other defective proteins so they can’t form those toxic protein clumps.”
Interestingly, earlier this month Cuervo’s team reported that, for the first time, they had isolated lysosomes from the brains of Alzheimer’s disease patients and observed that reduction in the number of LAMP2 receptors causes loss of CMA in humans, just as it does in animal models of Alzheimer’s.
Through their studies now reported in Cell, the researchers tested CA in two different mouse models of Alzheimer’s disease. In both disease mouse models, oral doses of CA administered over 4–6 months led to improvements in memory, depression, and anxiety, such that the treated animals resembled or closely resembled healthy, control mice. Walking ability significantly improved in the animal model in which it was a problem. The drug also significantly reduced levels of tau protein and protein clumps in the brain neurons of both animal models, compared with the neurons of untreated animals.
“Importantly, animals in both models were already showing symptoms of disease, and their neurons were clogged with toxic proteins before the drugs were administered,” Cuervo pointed out. “This means that the drug may help preserve neuron function even in the later stages of disease.” The scientists further stated, “Even at a symptomatic stage, activation of CMA led to strikingly reduced ß-amyloid and tau pathologies as well as glial activation.”
The authors stated, “… we demonstrate that chemical upregulation of CMA in two different mouse models of AD, with tau pathology or combined tau and ß-amyloid pathologies, reduces brain pathology and improves disease phenotype… our results highlight that pharmacological CMA activation using a clinically relevant design has a beneficial effect on AD-related pathology.”
Encouragingly, treatment with CA did not appear to harm other organs even when given daily for extended periods of time. Cuervo continued, “We were also very excited that the drug significantly reduced gliosis—the inflammation and scarring of cells surrounding brain neurons. Gliosis is associated with toxic proteins and is known to play a major role in perpetuating and worsening neurodegenerative diseases.”
The team concluded, “Our findings highlight the contribution of CMA to neuronal proteostasis, demonstrate that CMA deficiency in the aging brain is an aggravating factor in the onset of neurodegenerative diseases, and provide proof of concept for the value of targeting CMA as therapeutic strategy in these conditions.” Cuervo and Gavathiotis have teamed up with Life Biosciences of Boston, Massachusetts, to find Selphagy Therapeutics, which is currently developing CA and related compounds for treating Alzheimer’s and other neurodegenerative diseases.