New Insights Into the Aging Brain

Summary: A new study reports klotho, a protein associated with longevity, acts as a gatekeeper that helps shield the brain from the peripheral immune system.

Source: Gladstone Institutes.

The protein klotho has been shown to promote longevity and counteract aging-related impairments. Having more klotho seems to allow for longer and healthier lives, whereas a depletion of this molecule accelerates aging and may contribute to age-related diseases. Curiously, within the brain, one structure contains vastly higher levels of klotho than all the others.

This structure is the choroid plexus, which comprises a complex assembly of cells that produce cerebrospinal fluid and form an important barrier between the central nervous system and the blood.

A group of scientists at the Gladstone Institutes, led by Lennart Mucke, MD, decided to investigate why the choroid plexus contains so much more klotho than other brain regions. In a new study published in the scientific journal PNAS, they showed that klotho functions as a gatekeeper that shields the brain from the peripheral immune system.

“We discovered, in mouse models, that klotho levels in the choroid plexus naturally decrease with age,” said Mucke, senior investigator and director of the Gladstone Institute of Neurological Disease. “We then mimicked this aging process by reducing levels of klotho in this structure experimentally, and we found that depleting this molecule increases brain inflammation.”

Mucke and his team further investigated the impact of this phenomenon on other brain regions. They discovered that in mice with less klotho in the choroid plexus, innate immune cells in an important memory center reacted more aggressively when other parts of the body were exposed to immune challenges that mimic infections.

“The barrier between the brain and the immune system seems to break down with low levels of klotho,” said Lei Zhu, a scientist in Mucke’s laboratory and first author of the study. “Our findings indicate that klotho helps keep that barrier closed. When levels of this molecule are depleted in the choroid plexus, the barrier becomes more porous and allows immune cells and inflammatory molecules to get through more easily.”

This type of increased response from innate immune cells can be detrimental, because they produce certain factors that have been shown to impair brain functions.

a brain
Researchers showed that klotho functions as a gatekeeper that shields the brain from the peripheral immune system. image is in the public domain.

“The molecular changes we observed in our study suggest that klotho depletion from the choroid plexus might contribute to cognitive decline in elderly people through brain ‘inflammaging’,” added Mucke, who is also a professor of neurology and neuroscience at UC San Francisco. “It could help explain, at least in part, why we often notice deteriorations in cognitive functions in hospitalized seniors when they have infections, such as pneumonia or urinary tract infections. This complication tends to be particularly prominent in patients with Alzheimer’s disease, in which inflammation has emerged as a major driver of pathology.”

Now that they’ve shown that klotho depletion from the choroid plexus leads to increased brain inflammation, Mucke and his team are planning their next set of experiments to determine whether increasing klotho levels in the choroid plexus can help suppress age-related cognitive decline.

About this neuroscience research article

Funding: National Institutes of Health, Ray and Dagmar Dolby Family Fund, Ruth L. Kirschstein National Research Service Award funded this study.

Source: Julie Langelier – Gladstone Institutes
Publisher: Organized by
Image Source: image is in the public domain.
Original Research: Open access research for “Klotho controls the brain–immune system interface in the choroid plexus” by Lei Zhu, Liana R. Stein, Daniel Kim, Kaitlyn Ho, Gui-Qiu Yu, Lihong Zhan, Tobias E. Larsson, and Lennart Mucke in PNAS. Published November 9 2018.

Cite This Article

[cbtabs][cbtab title=”MLA”]Gladstone Institutes”New Insights Into the Aging Brain.” NeuroscienceNews. NeuroscienceNews, 12 November 2018.
<>.[/cbtab][cbtab title=”APA”]Gladstone Institutes(2018, November 12). New Insights Into the Aging Brain. NeuroscienceNews. Retrieved November 12, 2018 from[/cbtab][cbtab title=”Chicago”]Gladstone Institutes”New Insights Into the Aging Brain.” (accessed November 12, 2018).[/cbtab][/cbtabs]


Klotho controls the brain–immune system interface in the choroid plexus

Located within the brain’s ventricles, the choroid plexus produces cerebrospinal fluid and forms an important barrier between the central nervous system and the blood. For unknown reasons, the choroid plexus produces high levels of the protein klotho. Here, we show that these levels naturally decline with aging. Depleting klotho selectively from the choroid plexus via targeted viral vector-induced knockout in Klothoflox/flox mice increased the expression of multiple proinflammatory factors and triggered macrophage infiltration of this structure in young mice, simulating changes in unmanipulated old mice. Wild-type mice infected with the same Cre recombinase-expressing virus did not show such alterations. Experimental depletion of klotho from the choroid plexus enhanced microglial activation in the hippocampus after peripheral injection of mice with lipopolysaccharide. In primary cultures, klotho suppressed thioredoxin-interacting protein-dependent activation of the NLRP3 inflammasome in macrophages by enhancing fibroblast growth factor 23 signaling. We conclude that klotho functions as a gatekeeper at the interface between the brain and immune system in the choroid plexus. Klotho depletion in aging or disease may weaken this barrier and promote immune-mediated neuropathogenesis.

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