Scientists from the Gladstone Institutes and the University of California, San Francisco report in the Journal of Neuroscience that raising levels of the life-extending protein klotho can protect against learning and memory deficits in a mouse model of Alzheimer's disease. Remarkably, this boost in cognition occurred despite the accumulation of Alzheimer-related toxins in the brain, such as amyloid-beta and tau.
Klotho decreases naturally with aging, which also leads to a decline in cognitive ability. An earlier study from these researchers revealed that having a genetic variant that increases klotho levels is associated with better cognition in normal, healthy individuals, and experimentally elevating klotho in mice enhances learning and memory. However, klotho's influence in the face of aging-related cognitive disorders like Alzheimer's disease was unclear.
To test klotho's protective capacity, the scientists created a mouse model of Alzheimer's disease that produced higher levels of this protein throughout the body. Ordinarily, Alzheimer's-model mice have cognitive deficits, abnormal brain activity, and premature death, but raising klotho levels ameliorated these problems. The cognition-enhancing effects of the protein were powerful enough to counteract the effects of Alzheimer-related toxins, whose levels were unchanged.
"It's remarkable that we can improve cognition in a diseased brain despite the fact that it's riddled with toxins," says lead author Dena Dubal, MD, PhD, an assistant professor of neurology and the David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease at UCSF. "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."
Klotho's benefits may be due to its effect on a certain type of neurotransmitter receptor in the brain, called NMDA, that is crucially involved in learning and memory. While Alzheimer's impairs NMDA receptors, the mice with klotho elevation maintained normal receptor levels. In addition, these mice had more GluN2B--a subunit of NMDA--than control animals. This increase may have contributed to the protective effects of klotho, counteracting the detrimental impact of Alzheimer-related toxicity on the brain.
"The next step will be to identify and test drugs that can elevate klotho or mimic its effects on the brain," says senior author Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease and the Joseph B. Martin Distinguished Professor of Neuroscience 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."
Other researchers on the study from the Gladstone Institutes and UCSF include Lei Zhu, Pascal Sanchez, Kurtresha Worden, Lauren Broestl, Erik Johnson, Kaitlyn Ho, Gui-Qiu Yu, Daniel Kim, and Alexander Betourne. Makoto Kuro-o from the University of Texas Southwestern Medical Center, Eliezer Masliah from the University of California, San Diego, and Carmela Abraham from Boston University School of Medicine also took part in this research.
Funding was provided by the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the American Federation of Aging Research (AFAR), a MetLife/AFAR Award, and gifts from the S.D. Bechtel, Jr. Foundation, the Coulter-Weeks Foundation, and the Bakar Family Foundation.
About the Gladstone Institutes
To ensure our work does the greatest good, the Gladstone Institutes focus on conditions with profound medical, economic, and social impact--unsolved diseases of the brain, the heart, and the immune system. Affiliated with the University of California, San Francisco, Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease.
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences, as well as a preeminent biomedical research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospital San Francisco.