New evidence uncovered by scientists at Johns Hopkins Medicine suggests that one root of Alzheimer's disease may be a simple imbalance in acid-alkaline—or pH—chemistry inside brain cells called astrocytes.
Astrocytes work to clear amyloid beta proteins from the spaces between neurons, but decades of evidence has shown that if the clearing process goes awry, amyloid proteins pile up around neurons, leading to the characteristic amyloid plaques and nerve cell degeneration that are the hallmarks of memory-destroying Alzheimer's disease.
For the new study, described online June 26 in Proceedings of the National Academy of Sciences, scientists gave drugs called histone deacetylase, or HDAC, inhibitors to pH-imbalanced mice cells engineered with a common Alzheimer's gene variant. The experiment successfully reversed the pH problem and improved the capacity for amyloid beta clearance.
HDAC inhibitors are approved by the U.S. Food and Drug Administration for use in people with certain types of blood cancers, but not in people with Alzheimer's.
"By the time Alzheimer's disease is diagnosed, most of the neurological damage is done, and it's likely too late to reverse the disease's progression," says Rajini Rao, professor of physiology at the Johns Hopkins University School of Medicine. "That's why we need to focus on the earliest pathological symptoms or markers of Alzheimer's disease, and we know that the biology and chemistry of endosomes is an important factor long before cognitive decline sets in."
Nearly 20 years ago, scientists at Johns Hopkins and New York University discovered that endosomes—circular compartments that ferry cargo within cells—are larger and far more abundant in brain cells of people destined to develop Alzheimer's disease. This hinted at an underlying problem with endosomes that could lead to an accumulation of amyloid protein in spaces around neurons, Rao says.
To shuttle their cargo from place to place, endosomes use chaperones—proteins that bind to specific cargo and bring them back and forth from the cell's surface. Whether and how well this binding occurs depends on the proper pH level inside the endosome, a delicate balance of acidity and alkalinity, or acid and base, that makes endosomes float to the surface and slip back down into the cell.
Researchers cautioned that most HDAC inhibitors cannot cross the blood-brain barrier, a significant challenge to the direct use of the drugs for brain disorders. The scientists say they are planning additional experiments to see if HDAC inhibitors have a similar effect in lab-grown astrocytes from Alzheimer's patients, and that there is the potential to design HDAC inhibitors that can cross the barrier.
However, the scientists note that even before those experiments can happen, far more research is needed to verify and explain the precise relationship between amyloid proteins and Alzheimer's disease, which affects an estimated 50 million people worldwide. To date, there is no cure and no drugs that can predictably or demonstrably prevent or reverse Alzheimer's disease symptoms.Read more from Hopkins Medicine