Klotho Protein Fragment Improves Brain Function, Resilience in Mice; May Eventually Benefit Parkinson’s Patients

The naturally-occurring protein α-klotho improves cognition and brain resilience in mice, and may have potential benefits for Parkinson’s disease (PD) and Alzheimer’s disease (AD), researchers showed.

The study, ”Peripheral Elevation of a Klotho Fragment Enhances Brain Function and Resilience in Young, Aging, and α-Synuclein Transgenic Mice,” appeared in the journal Cell Reports.

The research was led by Dena B. Dubai, an MD and PhD, from the Department of Neurology in the Biomedical Sciences Graduate Program and Weill Institute for Neurosciences at University of California, San Francisco.

Current research aims at developing more effective and/or alternate therapies for age-related neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Delaying aging or increasing the resilience of the brain both represent potential successful strategies.

The klotho protein has several functions, including the regulation of insulin. It is produced in the kidneys and the brain and circulates in the bloodstream as a hormone.

Researchers have shown an association between klotho levels and aging in animal models and humans. Whereas higher levels of klotho, such as that derived from genetic variation in humans, increases lifespan, lower levels of the protein decrease it and are observed in aged organisms, neurodegenerative diseases, or chronic stress.

Klotho has also been found to enhance cognition and resilience of neurons in mice independent of age. Of note, studies have shown that lifelong and widespread increased production of klotho potentiates neural resilience and improves cognition in a mouse model of AD.

Studies in humans have shown that increased klotho levels in the serum are associated with other benefits beyond cognition, such as better connectivity in the cerebral cortex (an important area in learning and memory), and improved physical performance in aging.

Alpha-synuclein is a protein located at the cell membrane, whose excessive production inhibits release of molecules from the cells. The protein is key in Parkinson’s and also contributes to Alzheimer’s. Therefore, therapeutic approaches targeting α-synuclein could improve the outcome of these diseases.

The scientists used a variety of approaches to study whether a klotho protein fragment (αKL-F) could improve cognition in mice with low levels of the protein (aged mice), normal levels (young mice), or cognitive dysfunction (those with enhanced levels of α-synuclein).

The results showed that αKL-F, administered peripherally, improved cognition quickly — after four days — and lasted for more than two weeks in young mice. This improvement was even quicker in aged mice (two days). As for the mice with exaggerated levels of α-synuclein, αKL-F improved their motor and cognitive impairments. The scientists also observed that αKL-F did not change α-synuclein levels, which means the improved brain function comes from increased neuronal resilience.

The research also showed that αKL-F did not cross the blood-brain barrier, which means that its effects on brain function were not a result of direct stimulation. As for the molecular mechanisms involved, the study showed that αKL-F treatment induced glutamatergic signaling, a crucial excitatory type of communication between neurons.

Overall, the results suggest that “peripheral αKL-F treatment is sufficient to induce neural enhancement and resilience in mice and may prove therapeutic in humans,” the researchers wrote.

Future studies are needed to understand “the direct target of αKL-F, the relevant and causal peripheral mechanisms linked to that target,” and how peripheral αKL-F is able to act on the brain without crossing the blood-brain barrier.