More than five million senior citizens across the United States suffer from Alzheimer’s disease, and as more and more baby boomers turn 65, that number is expected to increase significantly. The staggering costs of caring for memory-impaired seniors who need assistance with daily living can strain the personal resources of families as well as the publicly financed Medicare system. Preventing, slowing, or stopping late-onset Alzheimer’s disease, estimated to affect one in three elderly Americans, has become a priority, prompting President Obama to boost research funding as part of a historic and ambitious plan, the National Alzheimer’s Project. Through observations of genes, proteins, and gum disease, these three Boston University researchers are at the forefront of efforts aimed at identifying risk factors and developing new pathways to therapeutic targets.
Klotho, a protein produced by brain cells, may play a crucial role in Alzheimer’s disease (AD), multiple sclerosis (MS), and other neurodegenerative diseases, as well as in healthy aging.
In a paper published in the journal Glia in 2008, Carmela R. Abraham, professor of biochemistry and medicine, and her colleagues found that Klotho proteins, shown by other researchers to suppress tumors and aging, decline in the brain as mammals grow older.
In further studies, Cidi Chen, research assistant professor in Abraham’s lab, and other collaborators identified Klotho as an important factor in the health of the brain’s white matter, which contains nerve fibers called axons that are covered by fatty myelin sheaths that give the white matter its light color. Klotho helps to keep the myelin sheaths around the axons healthy. Myelin, an insulating material that allows for rapid communication between nerve cells, is vital for learning, memory, and survival mechanisms like recognizing the need to pull a hand away from a hot stove.
“When the mice don’t have Klotho, they have abnormal myelin,” Abraham says. “This is proof that Klotho has an important function in oligodendrocytes, the brain cells that produce myelin.”
But Klotho is beneficial to more than oligodendrocytes. Ella Zeldich, a postdoctoral fellow in the Abraham lab, found that pretreating neurons with Klotho before feeding them with toxic amounts of glutamate, a key compound in cellular metabolism, in petri dishes was able to rescue the neurons from cell death. Neurons and their axons die from oxidative stress induced by glutamate toxicity in most, if not all, neurodegenerative diseases. Multiple sclerosis, an inflammatory disease in which the immune system attacks and damages myelin, primarily affects women and young adults.
After Abraham discovered that Klotho levels decline with age and disease, she searched for and identified small molecule compounds that would increase the production of the neuroprotective Klotho protein in the brain, creating the basis for developing therapeutic drugs. Drugs that enhance Klotho may be the key to the many diseases that have confounded researchers. “If we can develop such compounds, they may be beneficial for cancer, MS, and Alzheimer’s,” she says.
Abraham has dedicated 33 years of research to Alzheimer’s disease and normal brain aging. She received a $50,000 BU Ignition Award in 2012 to continue her research on Klotho; she is also the recipient of funding from the National Institute on Aging, the Alzheimer’s Association, and the Alzheimer’s Drug Discovery Foundation. She won the Neurosciences Education & Research Foundation Award for Outstanding Promise as a Young Alzheimer Investigator in 1989 and the Alzheimer’s Association’s highest awards—the Zenith Award in 1994 and the Temple Award in 1999.
Her goal, she says, is to take her work from research to therapy, “if we can have a drug developed by the end of my professional life, it will be very, very rewarding.”
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