{"id":132707,"date":"2024-12-03T04:21:53","date_gmt":"2024-12-02T21:21:53","guid":{"rendered":"https:\/\/hotvideos24.online\/?p=132707"},"modified":"2024-12-03T04:21:53","modified_gmt":"2024-12-02T21:21:53","slug":"ketone-bodies-clear-damaged-proteins-in-the-brain","status":"publish","type":"post","link":"https:\/\/hotvideos24.online\/?p=132707","title":{"rendered":"Ketone Bodies Clear Damaged Proteins in the Brain"},"content":{"rendered":"<p> <script async src=\"https:\/\/pagead2.googlesyndication.com\/pagead\/js\/adsbygoogle.js?client=ca-pub-3711241968723425\"\r\n     crossorigin=\"anonymous\"><\/script>\r\n<ins class=\"adsbygoogle\"\r\n     style=\"display:block\"\r\n     data-ad-format=\"fluid\"\r\n     data-ad-layout-key=\"-fb+5w+4e-db+86\"\r\n     data-ad-client=\"ca-pub-3711241968723425\"\r\n     data-ad-slot=\"7910942971\"><\/ins>\r\n<script>\r\n     (adsbygoogle = window.adsbygoogle || []).push({});\r\n<\/script><br \/>\n<\/p>\n<div>\n<p><strong>Summary: <\/strong>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 \u03b2-hydroxybutyrate alters the solubility of misfolded proteins, facilitating their removal and reducing pathological aggregation.<\/p>\n<p>Tests in mouse models of Alzheimer\u2019s 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.<\/p>\n<p><strong>Key Facts<\/strong><\/p>\n<ul class=\"wp-block-list\">\n<li>Ketone bodies directly bind to misfolded proteins, enhancing their clearance via autophagy.<\/li>\n<li>Mice treated with ketone esters displayed reduced aggregation of insoluble brain proteins.<\/li>\n<li>Similar metabolites tested showed effects equal to or better than \u03b2-hydroxybutyrate.<\/li>\n<\/ul>\n<p><strong>Source: <\/strong>Buck Institute<\/p>\n<p><strong>Ketone bodies, produced by the body to provide fuel during fasting, have roles in regulating cellular processes and aging mechanisms beyond energy production. <\/strong><\/p>\n<p>Research at the Buck Institute shows that ketone bodies can best be understood as powerful signaling metabolites affecting brain function in aging and Alzheimer\u2019s disease.<\/p>\n<p>A new study demonstrates that ketone bodies and similar metabolites have profound effects on the proteome and protein quality control in the brain.<\/p>\n<figure class=\"wp-block-image size-full\"><picture fetchpriority=\"high\" decoding=\"async\" class=\"wp-image-106638\"><source type=\"image\/webp\" srcset=\"https:\/\/neurosciencenews.com\/files\/2024\/12\/ketone-bodies-autophagy-neurosicence.jpg.webp 1200w, https:\/\/neurosciencenews.com\/files\/2024\/12\/ketone-bodies-autophagy-neurosicence-300x200.jpg.webp 300w, https:\/\/neurosciencenews.com\/files\/2024\/12\/ketone-bodies-autophagy-neurosicence-770x513.jpg.webp 770w, https:\/\/neurosciencenews.com\/files\/2024\/12\/ketone-bodies-autophagy-neurosicence-1155x770.jpg.webp 1155w, https:\/\/neurosciencenews.com\/files\/2024\/12\/ketone-bodies-autophagy-neurosicence-370x247.jpg.webp 370w, https:\/\/neurosciencenews.com\/files\/2024\/12\/ketone-bodies-autophagy-neurosicence-293x195.jpg.webp 293w, https:\/\/neurosciencenews.com\/files\/2024\/12\/ketone-bodies-autophagy-neurosicence-150x100.jpg.webp 150w\" sizes=\"(max-width: 1200px) 100vw, 1200px\"\/><img fetchpriority=\"high\" decoding=\"async\" width=\"1200\" height=\"800\" src=\"https:\/\/neurosciencenews.com\/files\/2024\/12\/ketone-bodies-autophagy-neurosicence.jpg\" alt=\"This shows a neuron.\" srcset=\"https:\/\/neurosciencenews.com\/files\/2024\/12\/ketone-bodies-autophagy-neurosicence.jpg 1200w, https:\/\/neurosciencenews.com\/files\/2024\/12\/ketone-bodies-autophagy-neurosicence-300x200.jpg 300w, https:\/\/neurosciencenews.com\/files\/2024\/12\/ketone-bodies-autophagy-neurosicence-770x513.jpg 770w, https:\/\/neurosciencenews.com\/files\/2024\/12\/ketone-bodies-autophagy-neurosicence-1155x770.jpg 1155w, https:\/\/neurosciencenews.com\/files\/2024\/12\/ketone-bodies-autophagy-neurosicence-370x247.jpg 370w, https:\/\/neurosciencenews.com\/files\/2024\/12\/ketone-bodies-autophagy-neurosicence-293x195.jpg 293w, https:\/\/neurosciencenews.com\/files\/2024\/12\/ketone-bodies-autophagy-neurosicence-150x100.jpg 150w\" sizes=\"(max-width: 1200px) 100vw, 1200px\"\/> <\/picture><figcaption class=\"wp-element-caption\">While acknowledging that other mechanisms like energy supply are also important to brain health, Newman calls the discovery new biology. Credit: Neuroscience News<\/figcaption><\/figure>\n<p>Publishing in\u00a0<em>Cell Chemical Biology,\u00a0<\/em>Buck Institute scientists, working in mouse models of Alzheimer\u2019s disease and aging, and in the nematode\u00a0<em>C. elegans,<\/em>\u00a0reveal the ketone body \u03b2-hydroxybutyrate interacts directly with misfolded proteins, altering their solubility and structure so they can be cleared from the brain through the process of autophagy.<\/p>\n<p>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.<\/p>\n<p>Senior author\u00a0John Newman, MD, PhD,\u00a0an 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.\u00a0<\/p>\n<p>\u201cNow we know that\u2019s not the whole story,\u201d he said. \u00a0\u201cKetone bodies interact with damaged and misfolded proteins directly, making them insoluble so they can be pulled from the cell and recycled.\u201d\u00a0<\/p>\n<p>While acknowledging that other mechanisms like energy supply are also important to brain health, Newman calls the discovery new biology.<\/p>\n<p>\u201cIt\u2019s a new link between metabolism in general, ketone bodies and aging,\u201d he said.<\/p>\n<p>\u201cDirectly linking changes in a cell\u2019s metabolic state to changes in the proteome is really exciting.\u201d<\/p>\n<p>Noting that ketone bodies are easy to manipulate experimentally and therapeutically, Newman adds, \u201cThis might be a powerful avenue to assist with global clearing of damaged proteins.<\/p>\n<p>\u201cWe\u2019re just scratching the surface as to how this might be applied to brain aging and neurodegenerative disease.\u201d\u00a0<\/p>\n<p>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.<\/p>\n<p>The work also highlights the power of the Buck\u2019s collaborative environment.<\/p>\n<p>The\u00a0Schilling lab\u00a0generated detailed proteome-wide solubility maps from both the test tube and mouse experiments.<\/p>\n<p>To test if the solubility changes caused by ketone bodies helped improve models of pathological aggregation, the\u00a0\u00a0Lithgow lab\u00a0fed ketone bodies to tiny nematode worms that were genetically modified to express the human equivalent of amyloid beta, which causes amyloid plaques.<\/p>\n<p> \u201cThe amyloid beta affects muscles and paralyzes the worms,\u201d says Sidharth Madhavan, a PhD candidate and lead author on the study.<\/p>\n<p>\u201cOnce 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.\u201d\u00a0\u00a0<\/p>\n<p>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.<\/p>\n<p>Newman says the study highlights a new form of metabolic regulation of protein quality control.<\/p>\n<p>\u201cThis is not just about ketone bodies,\u201d he said.<\/p>\n<p>\u201cWe tested similar metabolites in test tubes and a bunch of them had similar effects. In some cases, they performed better than \u03b2-hydroxybutyrate. It\u2019s beautiful to imagine that changing metabolism results in this symphony of molecules cooperating together to improve brain function.\u201d<\/p>\n<p><strong>Funding: <\/strong>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.<\/p>\n<h2 class=\"wp-block-heading\">About this neuroscience research news<\/h2>\n<p class=\"has-background\" style=\"background-color:#ffffe8\"><strong>Author: <\/strong><a href=\"http:\/\/neurosciencenews.com\/cdn-cgi\/l\/email-protection#3e554c5b5c575252514a7e5c4b5d5557504d4a574a4b4a5b10514c59\" target=\"_blank\" rel=\"noreferrer noopener\">Kris Rebillot<\/a><br \/><strong>Source:<\/strong><a href=\"https:\/\/buckinstitute.org\" target=\"_blank\" rel=\"noreferrer noopener\"><strong> <\/strong>Buck Institute<\/a><br \/><strong>Contact: <\/strong>Kris Rebillot \u2013 Buck Institute<br \/><strong>Image: <\/strong>The image is credited to Neuroscience News<\/p>\n<p class=\"has-background\" style=\"background-color:#ffffe8\"><strong>Original Research: <\/strong>Open access.<br \/>\u201c<a href=\"https:\/\/dx.doi.org\/10.1016\/j.chembiol.2024.11.001\" target=\"_blank\" rel=\"noreferrer noopener\">B-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer\u2019s disease brain<\/a>\u201d by John Newman et al. <em>Cell Chemical Biology<\/em><\/p>\n<hr class=\"wp-block-separator has-text-color has-pale-cyan-blue-color has-alpha-channel-opacity has-pale-cyan-blue-background-color has-background\"\/>\n<p><strong>Abstract<\/strong><\/p>\n<p><strong>B-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer\u2019s disease brain<\/strong><\/p>\n<p>Ketone bodies, small molecules that provide lipid-derived energy to cells during fasting, have been linked to various mechanisms of brain aging and increased healthy longevity in mice, and other fasting metabolism mechanisms have been linked to proteostasis.<\/p>\n<p>These data fill an important puzzle piece in the literature on pathogenic protein clearance under varying metabolic states.<\/p>\n<p>Here, we provide a direct molecular mechanism for the regulation of misfolded proteins by ketone bodies and related metabolites.<\/p>\n<p>While many factors can affect protein solubility\u00a0<em>in\u00a0vitro<\/em>, we showed that this mechanism is robust and reproducibly not dependent on covalent protein modification, pH, or solute load.<\/p>\n<p>Importantly, we reproduced the\u00a0<em>ex\u00a0vivo<\/em>\u00a0effect\u00a0<em>in\u00a0vivo<\/em>, using a ketone ester to indirectly deliver exogenous R-\u03b2HB to the mouse brain via hepatic metabolism to R-\u03b2HB and physiological transport of R-\u03b2HB into the brain without other exogenous biochemical alterations.<\/p>\n<p>R-\u03b2HB insolubilization targets that we identified\u00a0<em>ex\u00a0vivo<\/em>\u00a0strongly overlap with targets found\u00a0<em>in\u00a0vivo<\/em>, supporting the similarity of mechanism between the\u00a0<em>ex\u00a0vivo<\/em>\u00a0and\u00a0<em>in\u00a0vivo<\/em>\u00a0systems.<\/p>\n<p>We validated the physiological relevance of the mechanism by showing rescue in cell-based and\u00a0<em>C.\u00a0elegans<\/em>\u00a0models of amyloid-\u03b2 proteotoxicity.<\/p>\n<p>Given that proteostatic mechanisms like autophagy are known to be activated by nutrient deprivation, it is unsurprising that evolutionary pressures would encourage the clearance of pathogenic proteins during ketosis to promote cellular health in organisms seeking additional substrate for ATP production.<\/p>\n<p>In this situation, ketone bodies are janitors of damaged proteins, chaperoning away molecular waste so organisms can operate at peak molecular fitness.<\/p>\n<p>This mechanism can be leveraged for therapeutic development in aging and NDDs, including via pharmacological approaches for which we provide proof of principle with BH-BD.<\/p>\n<p>Understanding the molecular mechanisms of metabolism is an essential aspect of the future of accessible therapeutic interventions in aging and NDDs.<\/p>\n<p> <!-- Form created by Optin Forms plugin by WPKube: create beautiful optin forms with ease! 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