By: Shiv Jhattu
Researchers have developed an experimental drug that reverses key symptoms of Alzheimer’s in mice. The drug stimulates a cellular clean-up mechanism that eliminates unwanted proteins by digesting and recycling them. Co-study leader Ana Maria Cuervo. MD, Ph.D. says that “discoveries in mice don’t always translate to humans, especially in Alzheimer’s disease”. She continues by saying “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”. This suggests that the drug might also work for humans.
Dr. Cuervo found this cell-cleaning process in the 1990s and it is known as chaperone-mediated autophagy (CMA). On the downside, CMA becomes less efficient as people age. This increases the risk of accumulation of unwanted proteins, specifically, they can accumulate together into clumps of insoluble protein that can damage cells. Alzheimer’s and all other neurodegenerative diseases are characterized by the presence of toxic proteins in patients’ brains. Loss of CMA in neurons is directly linked to contributing to Alzheimer’s and vice versa. The findings suggest that drugs for revving up CMA may be a possible way to treat neurodegenerative diseases.
Cuervo’s team’s first look at whether impaired CMA contributes to Alzheimer’s was a lengthy and precise process. They genetically engineered a mouse to have excitatory brain neurons without CMA. This led to the discovery that the absence of CMA in only one type of brain cell causes short-term memory loss, impaired walking, and other problems related to rodent Alzheimer’s. It also disrupted proteostasis (cells’ ability to regulate the proteins they contain), which causes normally soluble proteins to become insoluble and risk clumping into toxic aggregates. Cuervo also suspected that Alzheimer’s itself impairs CMA. In a mouse with Alzheimer’s, it was found the CMA activity was significantly lower in the hippocampus- the area for memory and learning. They also looked at single-cell RNA-sequencing data from neurons obtained postmortem from the brains of Alzheimer’s patients and healthy patients. They found that the CMA activity was inhibited in people within the early stages of Alzheimer’s and further inhibited in people with a more advanced diagnosis of Alzheimer’s.
“By the time people reach the age of 70-80, 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 the CMA deficiency interacts synergistically with Alzheimer’s pathology to greatly accelerate disease progression” says Dr. Cuervo. CMA can still digest defective proteins but becomes much weaker; the experimental drug reinvigorates 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. They take these cells to the lysosomes which digest and recycle waste material. To get the cells into lysosomes, the chaperones must first place the material onto a protein receptor called LAMP2A that sprouts from the membranes of lysosomes. The more LAMP2A receptors on lysosomes, the greater the CMA activity. The new drug, called CA, works by increasing these LAMP2A receptors. You produce the same amount of these receptors throughout life, but as you age, the receptors deteriorate faster. This means that older people have less of them available. CA restores LAMP2A to levels present in younger populations, making CMA able to get rid of defective proteins. Reduction of LAMP2 receptors also causes loss of CMA in humans.
The researchers proceeded to test CA in two different mouse models of Alzheimer’s disease. In both, oral doses of the drug given for 4-6 months led to improvements in memory, depression and anxiety. This made the affected mice resemble healthy mice. Importantly, both models were already showing symptoms, meaning they were in later stages of the disease, yet the drug still worked meaning it could be beneficial for later stages of human Alzheimer’s as well. The drug also significantly reduced gliosis (inflammation and scarring of cells surrounding brain neurons) which is known for perpetuating and worsening neurodegenerative diseases. CA also did not appear to harm other organs even when given daily for long periods of time.
References:
"Experimental Drug Shows Potential Against Alzheimer's Disease: Removing 'Garbage' From Brain Cells Improves Memory In Mice". Sciencedaily, 2021, https://www.sciencedaily.com/releases/2021/04/210422150402.htm.
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