A key focus for medical scientists working to prevent or potentially treat Alzheimer's is coming up with ways to avoid the buildup of toxic proteins in the brain, which could include the use of ultrasound or maybe even regular deep sleep. A team at the Albert Einstein College of Medicine has uncovered another promising pathway, discovering that an experimental drug can supercharge a natural cellular cleaning mechanism to rid mice of these unwanted waste products, and reverse key symptoms of the disease.
At the heart of the research is a cellular cleaning process called chaperone-mediated autophagy (CMA), which sniffs out unwanted proteins in the body and digests and recycles them. Professor of developmental and molecular biology Ana Maria Cuervo discovered this CMA system in the 1990s and, having learned that it becomes less efficient as people age, drew up a study to investigate its potential links to Alzheimer's.
Cuervo and her team started by genetically engineering mice to feature excitatory brain neurons that lacked CMA, which led to a range of Alzheimer's-like symptoms, including short-term memory loss and impaired walking. This also disrupted the cells' ability to regulate the proteins inside them, causing what would normally be soluble proteins to become insoluble and prone to clumping.
Next, the team looked at the other side of this equation, investigating how Alzheimer's disease might impair the function of CMA. This part of the study involved what is considered to be a hallmark of the disease, the protein tau, which tends to clump together and form neurofibrillary tangles. These tangles are thought to help drive the neurodegeneration associated with the condition.
The scientists used mice engineered to produce defective copies of tau proteins, and examined their impact on CMA activity in neurons of the hippocampus, the part of the brain associated with memory and learning. CMA activity was found to be significantly reduced in these neurons, compared to a group of control animals.
To investigate whether Alzheimer's has similar effects in humans, the scientists looked at single-cell RNA-sequencing data on neurons collected from the brains of deceased Alzheimer's patients. Compared to a control group of healthy subjects, these subjects indeed exhibited suppressed CMA activity, with the more advanced the disease, the greater the damage.
“By the time people reach the age of 70 or 80, CMA activity has usually decreased by about 30 percent compared to when they were younger,” says Dr. 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.”
Armed with this new knowledge, the scientists developed a drug to breathe new life into the CMA process. Normally, CMA involves chaperone proteins that bind to damaged and defective proteins in cells, but to digest and recycle these proteins, the chaperones need to latch onto protein receptors called LAMP2A. This process deteriorates as we age, but the novel drug developed by the team boosts the amount of these LAMP2A receptors and restores them to youthful levels, and therefore allows for greater CMA activity.
Called CA, the drug was tested in two mouse models of Alzheimer's via oral doses over four to six months. Both groups of mice showed improvements in memory, depression and anxiety and closely resembled healthy mice at the end of the experiment. The treatment also improved walking ability in mice suffering from mobility issues, and in both groups, tau levels and protein clumps were significantly reduced.
“Importantly, animals in both models were already showing symptoms of disease, and their neurons were clogged with toxic proteins before the drugs were administered,” says Dr. Cuervo. “This means that the drug may help preserve neuron function even in the later stages of disease. 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 researchers have created a spin-off company to work on the development of CA into a clinical treatment for Alzheimer's and similar conditions. While aware of the limitations of their research in mice, the fact that they uncovered evidence of similar processes at play in humans offers plenty of room for optimism.
“Discoveries in mice don’t always translate to humans, especially in Alzheimer’s disease,” says Cuervo. “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 research was published in the journal Cell.
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