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 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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American Society for Clinical Investigation
01-10-2023
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| Abstract | 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. |
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| AbstractList | 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 (QR2 is) to enable evaluation of chronic QR2 inhibition as a means to reduce biological age-related metabolic stress and cognitive decline. QR2 is 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 QR2 is 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 QR2 is as first-in-class drugs. 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.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. 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. 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 factorto 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. |
| Audience | Academic |
| Author | Maitland, Matthew Lévesque, Maxime Walker, Matthew Shklyar, Boris Shurrush, Khriesto Scherer, Gila R Subramanyam, Chakrapani David, Orit Lefker, Bruce Rosenblum, Kobi Gould, Nathaniel L Sharir, Haleli Lalzar, Maya Germain, Nicolas Albeck, Shira Pavesi, Tommaso Carvalho, Silvia Thakar, Darshit Amitai, Gabriel Sharma, Vijendra Avoli, Massimo Shilton, Brian Hazut, Neta Babaev, Ilana Lajoie, Gilles Kayyal, Haneen Edry, Efrat Khamaisy, Mohammad Peleg, Yoav Barr, Haim Elkobi, Alina Dym, Orly Foqara, Maria |
| AuthorAffiliation | 6 Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel 1 Sagol Department of Neurobiology, University of Haifa, Haifa, Israel 3 The Centre for Genetic Manipulation in the Brain, University of Haifa, Haifa, Israel 9 Montreal Neurological Institute-Hospital and Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada 2 Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israeli National Center for Personalized Medicine (GINCPM), Weizmann Institute of Science, Rehovot, Israel 5 Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada 7 Bioinformatics Service Unit and 8 Bioimaging Unit, Faculty of Natural Sciences, University of Haifa, Haifa, Israel 4 Department of Biomedical Sciences, University of Windsor, Windsor, Ontario, Canada |
| AuthorAffiliation_xml | – name: 3 The Centre for Genetic Manipulation in the Brain, University of Haifa, Haifa, Israel – name: 5 Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada – name: 4 Department of Biomedical Sciences, University of Windsor, Windsor, Ontario, Canada – name: 1 Sagol Department of Neurobiology, University of Haifa, Haifa, Israel – name: 9 Montreal Neurological Institute-Hospital and Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada – name: 8 Bioimaging Unit, Faculty of Natural Sciences, University of Haifa, Haifa, Israel – name: 2 Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israeli National Center for Personalized Medicine (GINCPM), Weizmann Institute of Science, Rehovot, Israel – name: 6 Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel – name: 7 Bioinformatics Service Unit and |
| Author_xml | – sequence: 1 givenname: Nathaniel L surname: Gould fullname: Gould, Nathaniel L organization: Sagol Department of Neurobiology, University of Haifa, Haifa, Israel – sequence: 2 givenname: Gila R surname: Scherer fullname: Scherer, Gila R organization: Sagol Department of Neurobiology, University of Haifa, Haifa, Israel – sequence: 3 givenname: Silvia surname: Carvalho fullname: Carvalho, Silvia organization: Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israeli National Center for Personalized Medicine (GINCPM), Weizmann Institute of Science, Rehovot, Israel – sequence: 4 givenname: Khriesto surname: Shurrush fullname: Shurrush, Khriesto organization: Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israeli National Center for Personalized Medicine (GINCPM), Weizmann Institute of Science, Rehovot, Israel – sequence: 5 givenname: Haneen surname: Kayyal fullname: Kayyal, Haneen organization: Sagol Department of Neurobiology, University of Haifa, Haifa, Israel – sequence: 6 givenname: Efrat surname: Edry fullname: Edry, Efrat organization: The Centre for Genetic Manipulation in the Brain, University of Haifa, Haifa, Israel – sequence: 7 givenname: Alina surname: Elkobi fullname: Elkobi, Alina organization: Sagol Department of Neurobiology, University of Haifa, Haifa, Israel – sequence: 8 givenname: Orit surname: David fullname: David, Orit organization: Sagol Department of Neurobiology, University of Haifa, Haifa, Israel – sequence: 9 givenname: Maria surname: Foqara fullname: Foqara, Maria organization: Sagol Department of Neurobiology, University of Haifa, Haifa, Israel – sequence: 10 givenname: Darshit surname: Thakar fullname: Thakar, Darshit organization: Sagol Department of Neurobiology, University of Haifa, Haifa, Israel – sequence: 11 givenname: Tommaso surname: Pavesi fullname: Pavesi, Tommaso organization: Sagol Department of Neurobiology, University of Haifa, Haifa, Israel – sequence: 12 givenname: Vijendra surname: Sharma fullname: Sharma, Vijendra organization: Department of Biomedical Sciences, University of Windsor, Windsor, Ontario, Canada – sequence: 13 givenname: Matthew surname: Walker fullname: Walker, Matthew organization: Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada – sequence: 14 givenname: Matthew surname: Maitland fullname: Maitland, Matthew organization: Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada – sequence: 15 givenname: Orly surname: Dym fullname: Dym, Orly organization: Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel – sequence: 16 givenname: Shira surname: Albeck fullname: Albeck, Shira organization: Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel – sequence: 17 givenname: Yoav surname: Peleg fullname: Peleg, Yoav organization: Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel – sequence: 18 givenname: Nicolas surname: Germain fullname: Germain, Nicolas organization: Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israeli National Center for Personalized Medicine (GINCPM), Weizmann Institute of Science, Rehovot, Israel – sequence: 19 givenname: Ilana surname: Babaev fullname: Babaev, Ilana organization: Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israeli National Center for Personalized Medicine (GINCPM), Weizmann Institute of Science, Rehovot, Israel – sequence: 20 givenname: Haleli surname: Sharir fullname: Sharir, Haleli organization: Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israeli National Center for Personalized Medicine (GINCPM), Weizmann Institute of Science, Rehovot, Israel – sequence: 21 givenname: Maya surname: Lalzar fullname: Lalzar, Maya organization: Bioinformatics Service Unit and – sequence: 22 givenname: Boris surname: Shklyar fullname: Shklyar, Boris organization: Bioimaging Unit, Faculty of Natural Sciences, University of Haifa, Haifa, Israel – sequence: 23 givenname: Neta surname: Hazut fullname: Hazut, Neta organization: Sagol Department of Neurobiology, University of Haifa, Haifa, Israel – sequence: 24 givenname: Mohammad surname: Khamaisy fullname: Khamaisy, Mohammad organization: Sagol Department of Neurobiology, University of Haifa, Haifa, Israel – sequence: 25 givenname: Maxime surname: Lévesque fullname: Lévesque, Maxime organization: Montreal Neurological Institute-Hospital and Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada – sequence: 26 givenname: Gilles surname: Lajoie fullname: Lajoie, Gilles organization: Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada – sequence: 27 givenname: Massimo surname: Avoli fullname: Avoli, Massimo organization: Montreal Neurological Institute-Hospital and Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada – sequence: 28 givenname: Gabriel surname: Amitai fullname: Amitai, Gabriel organization: Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israeli National Center for Personalized Medicine (GINCPM), Weizmann Institute of Science, Rehovot, Israel – sequence: 29 givenname: Bruce surname: Lefker fullname: Lefker, Bruce organization: Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israeli National Center for Personalized Medicine (GINCPM), Weizmann Institute of Science, Rehovot, Israel – sequence: 30 givenname: Chakrapani surname: Subramanyam fullname: Subramanyam, Chakrapani organization: Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israeli National Center for Personalized Medicine (GINCPM), Weizmann Institute of Science, Rehovot, Israel – sequence: 31 givenname: Brian surname: Shilton fullname: Shilton, Brian organization: Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada – sequence: 32 givenname: Haim surname: Barr fullname: Barr, Haim organization: Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israeli National Center for Personalized Medicine (GINCPM), Weizmann Institute of Science, Rehovot, Israel – sequence: 33 givenname: Kobi surname: Rosenblum fullname: Rosenblum, Kobi organization: The Centre for Genetic Manipulation in the Brain, University of Haifa, Haifa, Israel |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/37561584$$D View this record in MEDLINE/PubMed |
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| Title | Specific quinone reductase 2 inhibitors reduce metabolic burden and reverse Alzheimer's disease phenotype in mice |
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