Specific quinone reductase 2 inhibitors reduce metabolic burden and reverse Alzheimer's disease phenotype in mice

Biological aging can be described as accumulative, prolonged metabolic stress and is the major risk factor for cognitive decline and Alzheimer's disease (AD). Recently, we identified and described a quinone reductase 2 (QR2) pathway in the brain, in which QR2 acts as a removable memory constrai...

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Published in:	The Journal of clinical investigation Vol. 133; no. 19; pp. 1 - 16
Main Authors:	Gould, Nathaniel L, Scherer, Gila R, Carvalho, Silvia, Shurrush, Khriesto, Kayyal, Haneen, Edry, Efrat, Elkobi, Alina, David, Orit, Foqara, Maria, Thakar, Darshit, Pavesi, Tommaso, Sharma, Vijendra, Walker, Matthew, Maitland, Matthew, Dym, Orly, Albeck, Shira, Peleg, Yoav, Germain, Nicolas, Babaev, Ilana, Sharir, Haleli, Lalzar, Maya, Shklyar, Boris, Hazut, Neta, Khamaisy, Mohammad, Lévesque, Maxime, Lajoie, Gilles, Avoli, Massimo, Amitai, Gabriel, Lefker, Bruce, Subramanyam, Chakrapani, Shilton, Brian, Barr, Haim, Rosenblum, Kobi
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 01-10-2023
Subjects:	Advertising executives Age Aging Alzheimer Disease - drug therapy Alzheimer Disease - genetics Alzheimer's disease Amino acids Animal models Animals Biomedical research Brain Cell metabolism Cells Cognition & reasoning Cognitive ability Drinking water Drug therapy Genetic aspects Health aspects Hippocampus Hippocampus - metabolism Homeostasis Humans Kinases Melatonin Memory Metabolism Mice Microinjection Neurodegenerative diseases Neurons Neuroscience Oxidative Stress Oxidoreductases Pharmacology, Experimental Phenotype Phenotypes Phosphorylation Proteins Proteomes Quinone Quinone Reductases - antagonists & inhibitors Quinone Reductases - genetics Quinone Reductases - metabolism Rats Risk factors Stress, Physiological Israel Signal transduction Neurodegeneration Neuroscience
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Summary:	Biological aging can be described as accumulative, prolonged metabolic stress and is the major risk factor for cognitive decline and Alzheimer's disease (AD). Recently, we identified and described a quinone reductase 2 (QR2) pathway in the brain, in which QR2 acts as a removable memory constraint and metabolic buffer within neurons. QR2 becomes overexpressed with age, and it is possibly a novel contributing factor to age-related metabolic stress and cognitive deficit. We found that, in human cells, genetic removal of QR2 produced a shift in the proteome opposing that found in AD brains while simultaneously reducing oxidative stress. We therefore created highly specific QR2 inhibitors (QR2is) to enable evaluation of chronic QR2 inhibition as a means to reduce biological age-related metabolic stress and cognitive decline. QR2is replicated results obtained by genetic removal of QR2, while local QR2i microinjection improved hippocampal and cortical-dependent learning in rats and mice. Continuous consumption of QR2is in drinking water improved cognition and reduced pathology in the brains of AD-model mice (5xFAD), with a noticeable between-sex effect on treatment duration. These results demonstrate the importance of QR2 activity and pathway function in the healthy and neurodegenerative brain and what we believe to be the great therapeutic potential of QR2is as first-in-class drugs.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1558-8238 0021-9738 1558-8238
DOI:	10.1172/JCI162120