Ketone Bodies Clear Damaged Proteins in the Brain

 I'm sure your competent doctor has had a protocol on ketones for over a decade!

ketones (6 posts to February 2013)

NO? So, you don't have a functioning stroke doctor, do you?

Ketone Bodies Clear Damaged Proteins in the Brain

Summary: Ketone bodies, known for their role in energy metabolism during fasting, have been shown to directly interact with damaged proteins in the brain, aiding their clearance through autophagy. Researchers discovered that the ketone body β-hydroxybutyrate alters the solubility of misfolded proteins, facilitating their removal and reducing pathological aggregation.

Tests in mouse models of Alzheimer’s and aging confirmed these effects, with treated animals showing improvements in protein quality control and brain health. This breakthrough provides a new metabolic link to aging and neurodegeneration, offering a potential pathway for therapeutic applications.

Key Facts

• Ketone bodies directly bind to misfolded proteins, enhancing their clearance via autophagy.
• Mice treated with ketone esters displayed reduced aggregation of insoluble brain proteins.
• Similar metabolites tested showed effects equal to or better than β-hydroxybutyrate.

Source: Buck Institute

Ketone bodies, produced by the body to provide fuel during fasting, have roles in regulating cellular processes and aging mechanisms beyond energy production.

Research at the Buck Institute shows that ketone bodies can best be understood as powerful signaling metabolites affecting brain function in aging and Alzheimer’s disease.

A new study demonstrates that ketone bodies and similar metabolites have profound effects on the proteome and protein quality control in the brain.

While acknowledging that other mechanisms like energy supply are also important to brain health, Newman calls the discovery new biology. Credit: Neuroscience News

Publishing in Cell Chemical Biology, Buck Institute scientists, working in mouse models of Alzheimer’s disease and aging, and in the nematode C. elegans, reveal the ketone body β-hydroxybutyrate interacts directly with misfolded proteins, altering their solubility and structure so they can be cleared from the brain through the process of autophagy.

Previous studies have shown that boosting ketone bodies through diet, exercise and supplementation can be good for brain health and cognition, both in rodents and humans.

Senior author John Newman, MD, PhD, an assistant professor at the Buck, says many theorized that the ketone body-based improvements were caused by increased energy to the brain or a reduction in brain inflammation, with reported improvements in amyloid plaques in mouse models being an indirect by-product. 

“Now we know that’s not the whole story,” he said.  “Ketone bodies interact with damaged and misfolded proteins directly, making them insoluble so they can be pulled from the cell and recycled.” 

While acknowledging that other mechanisms like energy supply are also important to brain health, Newman calls the discovery new biology.

“It’s a new link between metabolism in general, ketone bodies and aging,” he said.

“Directly linking changes in a cell’s metabolic state to changes in the proteome is really exciting.”

Noting that ketone bodies are easy to manipulate experimentally and therapeutically, Newman adds, “This might be a powerful avenue to assist with global clearing of damaged proteins.

“We’re just scratching the surface as to how this might be applied to brain aging and neurodegenerative disease.” 

In addition to testing the changing solubility and structure of proteins in test tubes, the project also involved feeding a ketone ester to mice to confirm that the test tube results were reproduced in the brain. In mice, the ketone ester treatment resulted in clearance rather than pathological aggregation of insoluble proteins.

The work also highlights the power of the Buck’s collaborative environment.

The Schilling lab generated detailed proteome-wide solubility maps from both the test tube and mouse experiments.

To test if the solubility changes caused by ketone bodies helped improve models of pathological aggregation, the  Lithgow lab fed ketone bodies to tiny nematode worms that were genetically modified to express the human equivalent of amyloid beta, which causes amyloid plaques.

“The amyloid beta affects muscles and paralyzes the worms,” says Sidharth Madhavan, a PhD candidate and lead author on the study.

“Once they were treated with ketone bodies the animals recovered their ability to swim. It was really exciting to see such a dramatic impact in a whole animal.”  

Madhavan is now pursuing whether ketone bodies and related metabolites have similar effects outside the brain, such as in the gut. A key next step will be to test this new protein quality control mechanism in people to help guide how best to apply it in therapies, he adds.

Newman says the study highlights a new form of metabolic regulation of protein quality control.

“This is not just about ketone bodies,” he said.

“We tested similar metabolites in test tubes and a bunch of them had similar effects. In some cases, they performed better than β-hydroxybutyrate. It’s beautiful to imagine that changing metabolism results in this symphony of molecules cooperating together to improve brain function.”

Funding: This work was supported by the National Institutes of Health (NIH R01AG067333, NIA T32AG052374, NIA T32 AG000266, NIH R01AG067333-02S1), a sponsored research agreement from BHB Therapeutics, University of Southern California Provost Fellowship Funding, the Larry L. Hillblom Foundation, and Buck Institute institutional funding.

About this neuroscience research news

Author: Kris Rebillot
Source: Buck Institute
Contact: Kris Rebillot – Buck Institute
Image: The image is credited to Neuroscience News

Original Research: Open access.
“B-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer’s disease brain” by John Newman et al. Cell Chemical Biology

Drugs already in medicine cabinets may fight dementia, early data suggests

Preliminary, so you better start saving money to hire your own researchers on this.
https://arstechnica.com/science/2017/04/drugs-already-in-medicine-cabinets-may-fight-dementia-early-data-suggests/
Tried, true, and FDA-approved drugs for cancer and depression—already in medicine cabinets—may also be long-sought treatments for devastating brain diseases such as Alzheimer’s, Parkinson’s, and other forms of dementia, according to a new study in Brain, a Journal of Neurology.
The research is still in early stages; it only involved mouse and cell experiments, which are frequently not predictive of how things will go in humans. Nevertheless, the preliminary findings are strong, and scientists are optimistic that the drugs could one day help patients with progressive brain disease. Researchers are moving toward human trials. And this process would be streamlined because the drugs have already cleared safety tests. But even if the early findings hold up, it would still take years to reach patients.
In the preliminary tests, the two drugs—trazodone hydrochloride, used to treat depression and anxiety, and dibenzoylmethane (DBM), effective against prostate and breast tumors—could shut down a devastating stress response in brain cells, known to be critical for the progression of brain diseases. The drugs both protected brain cells and restored memory in mice suffering from brain diseases.
"We're excited by the potential of these findings from this well-conducted and robust study,” Doug Brown, of the Alzheimer's Society, told the BBC.
David Dexter, from Parkinson's UK, added that “if these studies were replicated in human clinical trials, both trazodone and DBM could represent a major step forward.”

Stressful stress response

For years, researchers have known that a stress response in cells, called “unfolded protein response,” or UPR, is involved in a bunch of neurodegenerative diseases. The response kicks in when there’s a buildup of unfolded or misfolded proteins. Typically, protein chains are folded into specific 3D structures that are often critical for their function in the body. But this folding goes awry in some neurodegenerative conditions, such as prion diseases, Alzheimer's disease, Parkinson's disease, and other forms of dementia.
When this happens, UPR kicks in. It shuts down protein production, tries to junk the botched proteins, and gets protein production machinery back in order. If all goes well, the cell can resume normal protein production. But if it doesn’t, UPR initiates apoptosis, aka cell suicide.
In neurodegenerative diseases, things don’t go well; UPR is over-activated, and brain cells start dying off. Scientists know that hampering UPR can protect brain cells and restore memory in mice engineered to mimic having Alzheimer's disease. But so far, all the compounds found to knock back UPR were highly toxic or highly insoluble (they don’t work as medicine).

Cut to the drugs

For a drug discovery shortcut, researchers at the University of Cambridge wondered: do we already have drugs that can interfere with UPR but just don’t know it? They screened a library of 1,040 FDA-approved drugs to find out.
Because UPR is highly conserved across animals, the researchers could use worms to screen the drugs. They initially found 20 drugs that seemed to have UPR-dampening effects. Upon further testing, they whittled down the list to five, then to two.
In further cell experiments, both trazodone and DBM inhibited a specific step in UPR and restored protein production. In mice, the drugs traversed the blood-brain barrier. When the researchers infected mice with a prion disease, clinically relevant doses of either drug held back neurological symptoms, boosted survival, and substantially reduced loss of brain cells in most of the infected mice. In mice that modeled a type of dementia, called frontotemporal dementia, both drugs could rescue the rodents’ memory and restore protein synthesis in brain cells.
“The two drugs were markedly neuroprotective,” the authors conclude. “These drugs therefore represent an important step forward in the pursuit of disease-modifying treatments for Alzheimer’s and related disorders.”
Trazodone, the authors note, is even already approved for use in the elderly. Clinical trials are the next step.
Brain, 2017. DOI: 10.1093/brain/awx074  (About DOIs).