Alzheimer’s disease (AD) is characterized by problems with the metabolism and maintenance of proteins in the brain. The study investigated the role of β-hydroxybutyrate (R-βHB), a ketone body produced by the liver, in controlling the solubility of brain proteins. The research revealed that R-βHB interacts directly with pathological proteins, such as amyloid-β, and can promote the degradation of insoluble proteins, offering a new therapeutic strategy to combat aging and AD.
Alzheimer’s disease (AD) continues to be one of the most impactful conditions in humans, posing a major challenge to medicine, with few effective therapies that can modify the course of the disease.
AD is characterized by two main problems in the brain: difficulties in energy metabolism and failure to maintain the balance of proteins within cells (called “proteostasis”). When metabolism and proteostasis do not function properly, brain cells begin to suffer damage.
This occurs both in sporadic cases (without familial causes) and in cases of AD related to genetic factors, such as apolipoprotein E (APOE) alleles, which are genetic variants associated with an increased risk of the disease.
These problems make AD an even greater challenge to treat, since the interactions between cellular metabolism and protein maintenance are still poorly understood. In addition, advanced age is the main risk factor for the development of AD.
Aging is often associated with a loss of proteostasis and dysregulation of cellular signals related to nutrients, among other molecular mechanisms known to be linked to metabolism.
A new line of research suggests that small molecules, such as metabolites, may link metabolism with aging-related processes, not only by fulfilling their primary function of providing energy, but also by interacting directly with proteins.
In this study, researchers at the Buck Institute for Research on Aging, USA, investigated how these metabolites can directly affect proteostasis in a cellular environment.
Ketone bodies are small molecules that are produced in the liver from lipids (fats) and include substances such as acetone, acetoacetate and (R)-β-hydroxybutyrate (R-βHB). The main function of ketone bodies is to provide energy to cells, especially during periods when the body does not have much glucose available, such as fasting, starvation, intense exercise or ketogenic diets.
Furthermore, ketone bodies can be administered externally, without changes in diet, for example, through compounds called ketone esters.
R-βHB is not only an energy source, but it also has the ability to bind to several proteins within cells, making modifications that affect how these proteins function.
These modifications include inhibition of enzymes that remove acetyl groups from histones (the proteins that help organize DNA), modification of proteins inside and outside the cell nucleus, inhibition of the NLRP3 inflammasome (a complex that is involved in the inflammatory response), and interaction with receptors on the surface of cells.
These binding effects can alter the function of proteins involved in many important cellular processes.
There are already several studies suggesting that ketogenic diets (rich in ketone bodies) may help with healthy aging and AD. In mouse models, a ketogenic diet has been shown to increase lifespan and improve memory in older mice.
In addition, ketone-rich diets and external ketone administration have improved cognitive and motor behavior in mice with AD.
Some early research in humans also suggests that ketogenic compounds may improve cognition in patients with mild to moderate AD.
One way ketone bodies are thought to help is through synaptic plasticity, meaning they may improve the brain’s ability to form new connections between neurons.
This has been observed in mouse models, both in normal older mice and in mouse models of AD. Although the exact mechanisms are not yet fully understood, there is evidence that ketone bodies help improve proteostasis, or the balance of proteins in the brain.
For example, R-βHB has been shown to prevent the toxic effects of amyloid-β protein (one of the proteins that forms plaques in the brains of AD patients). In addition, both the ketogenic diet and externally administered ketones help reduce the amount of these amyloid plaques in the brains of mouse models of AD.
The reduction of these plaques has also been observed with dietary interventions that induce the production of ketone bodies, such as calorie restriction and intermittent fasting.
Older mice fed non-obesogenic ketogenic diets showed improvements in synaptic plasticity, dendritic branching, and increased production of BDNF (brain-derived neurotrophic factor), a protein important for brain health, as a result of a restructuring of the synaptic proteome (the set of proteins at synapses, or communication points between neurons).
In addition, recent studies suggest that ketone bodies may also aid in the process of autophagy (the cellular clearance of damaged proteins, including proteins associated with AD, such as amyloid-β and tau).
Ketone bodies (specifically R-βHB) are known to regulate proteostasis, but how this happens is not yet fully understood. This study aims to identify how R-βHB interacts directly with proteins to regulate their solubility, and how it may be useful in combating AD-associated toxicity.
Proteostasis is crucial for brain function and is closely linked to aging and neurodegenerative diseases (NDDs) such as Alzheimer’s disease. When proteostasis fails, misfolded proteins begin to accumulate and form aggregates within the brain.
These aggregates are a key feature of AD, as misfolded soluble proteins, such as amyloid-β oligomers, can spread from cell to cell and contribute to disease progression.
Although the exact relationship between these soluble proteins and aggregates is not yet fully understood, it is possible that the insolubilization (or loss of solubility) of these proteins, especially if accompanied by their degradation, may act as a defense strategy for the brain against the damage caused by AD.
Therapies that use antibodies against soluble amyloid oligomers, such as lecanemab, have already demonstrated some clinical success.
In this study, for the first time, scientists identified a novel role for R-βHB in directly interacting with pathological proteins, such as amyloid-β1-42. They demonstrated how R-βHB and other related small molecule metabolites can ameliorate the toxicity of amyloid-β1-42, both in vitro (in mammalian cells) and in vivo (in C. elegans, a type of worm used as a model for the research) experiments.
C. elegans
To do this, they created libraries of protein targets from the brains of aged mice using a technique called data-independent acquisition mass spectrometry (DIA-MS).
This technique allowed them to identify the proteins most affected by R-βHB treatment and observe how they were related to neurodegeneration. They also performed experiments to see if R-βHB can help clear these insoluble proteins from the mouse brain.
The results indicate that R-βHB acts as a global regulator of cytosolic protein solubility, and that the clearance (or elimination) of these proteins can be facilitated by cellular protein degradation pathways.
In summary, this study shows that R-βHB may be a valuable tool in the treatment of AD by directly regulating proteostasis, and opens up new possibilities for therapeutic development focused on the metabolism and maintenance of cellular proteins, both in aging and in Alzheimer's disease.
READ MORE:
β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain
Sidharth S. Madhavan, Stephanie Roa Diaz, Sawyer Peralta, Mitsunori Nomura, Christina D. King, Kaya E. Ceyhan, Anwen Lin, Dipa Bhaumik, Anna C. Foulger, Samah Shah, Thanh Blade, Wyatt Gray, Manish Chamoli, Brenda Eap, Oishika Panda, Diego Diaz, Thelma Y. Garcia, Brianna J. Stubbs, Scott M. Ulrich, Gordon J. Lithgow, Birgit Schilling, Eric Verdin, Asish R. Chaudhuri, John C. Newman
Cell Chemical Biology. Published online December 2, 2024
DOI: 10.1016/j.chembiol.2024.11.001
Abstract:
Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). We identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility. βHB primarily provides ATP substrate during periods of reduced glucose availability, and regulates other cellular processes through protein interactions. We demonstrate βHB-induced protein insolubility is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a ketone ester. This mechanism is selective for pathological proteins such as amyloid-β, and exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity. We generate libraries of the βHB-induced protein insolublome using mass spectrometry proteomics, and identify common protein domains and upstream regulators. We show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain. These data indicate a metabolically regulated mechanism of proteostasis relevant to aging and AD.
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