February 26, 2015
Raising levels of a protein in mice that is linked to a longer life appears to help protect laboratory animals from the ravages of Alzheimer’s disease, scientists report. The findings offer new clues about how Alzheimer’s develops and could open up new avenues of research for a disease that is critically lacking in effective treatments.
The protein, known as klotho, named for one of the Greek Fates, has been linked in earlier studies to a longer life in both humans and mice. People who carry a variant form of the klotho gene, which causes more klotho protein to be produced, appear to have more gray matter in parts of the brain commonly affected by aging. In mice that had been specially bred to develop an Alzheimer’s-like illness, the protein also appears to protect against the memory and thinking problems associated with the disease when more of the protein is produced.
In the current study, published in the Journal of Neuroscience, researchers found that elevating levels of the normal klotho protein appeared to protect against dementia symptoms, even though the brains of the mice they used as models contained the toxic beta-amyloid plaques and tau deposits that are a hallmark of Alzheimer’s disease.
“It’s remarkable that we can improve cognition in a diseased brain despite the fact that it’s riddled with toxins,” said the lead author, Dr. Dena Dubal, an assistant professor of neurology at the University of California, San Francisco. “In addition to making healthy mice smarter, we can make the brain resistant to Alzheimer-related toxicity. Without having to target the complex disease itself, we can provide greater resilience and boost brain functions.”
In earlier studies, the researchers found that breeding mice that produced low amounts of the protein led to premature aging, heart disease, and declines in memory and thinking skills. Conversely, high-levels of the protein were tied to longevity and improved cognition.
This study looked at the effects of the protein in Alzheimer’s, using a strain of mice that had been bred to develop certain characteristics of the disease. The mice also produced high levels of klotho throughout the body, including in the brain.
The scientists found that even though the brains of the mice showed many of the signs of Alzheimer’s disease – including the buildup of beta-amyloid plaque and abnormal tau protein – the mice appeared to be protected from decline in learning and memory.
Scientists think that klotho may have beneficial effects on a brain receptor called NMDA that is critical for learning and memory. Alzheimer’s appears to target these receptors, while the protein appears to protect them from damage.
“The next step will be to identify and test drugs that can elevate klotho or mimic its effects on the brain,” said Dr. Lennart Mucke, the study’s senior author and director of the Gladstone Institute of Neurological Disease at UCSF. “We are encouraged in this regard by the strong similarities we found between klotho’s effects in humans and mice in our earlier study. We think this provides good support for pursuing klotho as a potential drug target to treat cognitive disorders in humans, including Alzheimer’s disease.”
It will likely be years, however, before scientists develop a drug for people that mimics the effects of klotho in the brain. Developing a drug for Alzheimer’s disease is a laborious and costly process involving years of research and testing, first in animals, then in people, to assure that it is safe and effective. Many drugs that have shown initial promise have failed to live up to expectations in later trials.
Source: Dena B. Dubal, Lei Zhu, Pascal E. Sanchez, et al: “Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice.” The Journal of Neuroscience, 11 February 2015, 35(6): 2358-2371; doi: 10.1523/JNEUROSCI.5791-12.2015