New Drug Boosts Brain Cell Cleanup to Combat Neurodegenerative Diseases

Researchers from Albert Einstein College of Medicine are excited with the recently published findings of an experimental drug that reversed key symptoms of Alzheimer’s disease in mice. 

The drug, developed by Ana Maria Cuervo, M.D., Ph.D. and her team, reinvigorates the cellular cleanup of the brain. When the 'garbage trucks' of the brain slow down and stop with age, particularly in neurodegenerative diseases like Alzheimer’s, the trash piles up. Alzheimer’s and all other neurodegenerative diseases are characterized by the buildup of toxic proteins in the brain. 

The vital cell-cleaning process was discovered by Cuervo in the 90s. Chaperone-mediated autophagy, CMA, becomes less efficient as people age, resulting in protein clumps that damage brain cells. Cuervo and her team proved that impaired CMA contributes to Alzheimer’s, with the reverse also true – Alzheimer's impairs CMA. CMA activity is somewhat inhibited in early stages of Alzheimer’s and greatly inhibited once the disease is advanced. 

"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," Cuervo said. "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." 

Armed with this knowledge, Cuervo and study co-leader Evris Gavathiotis, Ph.D., co-founded a startup under parent company Life Biosciences named Selphagy Therapeutics.  

Life Biosciences has “daughter” companies focused on eight areas they believe account for aging and age-related diseases: mitochondrial dysfunction; altered communication and inflammation; chromosomal instability; cellular senescence; loss of proteostasis; epigenetic alterations; stem cell exhaustion; and metabolism. Selphagy’s focus is on autophagy, recycling the garbage in the brain.  

Selphagy is developing a new drug, CA, that will revitalize CMA efficiency, energizing it again to take out the cellular trash. The drug also increases the number of LAMP2A receptors on the recycling lysosomes, making it easier for the CMA to ferry and drop off its cargo at the “recycling station."

"You produce the same amount of LAMP2A receptors throughout life," Cuervo said. "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." 

In mouse models, after 4 to 6 months on CA, improvements were seen in memory, depression and anxiety. Walking ability significantly improved as well. Treated Alzheimer’s model mice then closely resembled the healthy control mice. CA significantly reduced levels of tau protein, a well-known and studied Alzheimer’s target, and protein clumps in the treated animals, compared to the untreated mice. The drug also reduced gliosis, the inflammation and scarring of cells around brain neurons. Gliosis is a major player in perpetuating and worsening neurodegenerative diseases. 

Cuervo and Gavathiotis will continue developing CA and related compounds for Alzheimer’s and other neurodegenerative diseases within Selphagy Therapeutics. 

"Discoveries in mice don't always translate to humans, especially in Alzheimer's disease... 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," Cuervo said.