Protein Treatment Staves Off Alzheimer’s Disease Symptoms

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Alzheimer’s disease is the sixth leading cause of death in the United States, with over 1,200 individuals developing the disease every day. A new paper in the Journal of Neuroscience from lead author Dena Dubal of the University of California, San Francisco describes how manipulating levels of a protein associated with memory can stave off Alzheimer’s symptoms, even in the presence of the disease-causing toxins.

Klotho is a transmembrane protein associated with longevity. The body makes less of this protein over time, and low levels of klotho is connected to a number of diseases including osteoporosis, heart disease, increased risk of stroke, and decreased cognitive function. These factors lead to diminished quality of life and even early death.

Previous research has shown that increasing klotho levels in healthy mice leads to increased cognitive function. This current paper from Dubal’s team builds on that research by increasing klotho in mice who are also expressing large amounts of amyloid-beta and tau, proteins that are associated with the onset of Alzheimer’s disease. Remarkably, even with high levels of these toxic, disease-causing proteins, the mice with elevated klotho levels were able to retain their cognitive function.

“It’s remarkable that we can improve cognition in a diseased brain despite the fact that it’s riddled with toxins,” Dubal said in a press release. “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.”

The mechanism behind this cognitive preservation appears to be klotho interacting with a glutamate receptor called NMDA, which is critically important to synaptic transmission, thus influencing learning, memory, and executive function. Alzheimer’s disease typically damages these receptors, but the mice with elevated klotho were able to retain both NMDA function and cognition. Part of the success also appears to be due to the preservation of the NMDA subunit GluN2B, which existed in significantly larger numbers than the control mice. The mechanism and the results of this study will need to be investigated further before developing it into a possible treatment for humans in the future.

“The next step will be to identify and test drugs that can elevate klotho or mimic its effects on the brain,” added senior author Lennart Mucke from Gladstone Institutes. “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.”

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