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

  • J Clin Invest. 2023 Oct 2;133(19):e162120. doi: 10.1172/JCI162120.
Nathaniel L Gould  1 Gila R Scherer  1 Silvia Carvalho  2 Khriesto Shurrush  2 Haneen Kayyal  1 Efrat Edry  1  3 Alina Elkobi  1 Orit David  1 Maria Foqara  1 Darshit Thakar  1 Tommaso Pavesi  1 Vijendra Sharma  4 Matthew Walker  5 Matthew Maitland  5 Orly Dym  6 Shira Albeck  6 Yoav Peleg  6 Nicolas Germain  2 Ilana Babaev  2 Haleli Sharir  2 Maya Lalzar  7 Boris Shklyar  8 Neta Hazut  1 Mohammad Khamaisy  1 Maxime Lévesque  9 Gilles Lajoie  5 Massimo Avoli  9 Gabriel Amitai  2 Bruce Lefker  2 Chakrapani Subramanyam  2 Brian Shilton  5 Haim Barr  2 Kobi Rosenblum  1  3
Affiliations
  • 1. Sagol Department of Neurobiology, University of Haifa, Haifa, Israel.
  • 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.
  • 3. The Centre for Genetic Manipulation in the Brain, University of Haifa, Haifa, Israel.
  • 4. Department of Biomedical Sciences, University of Windsor, Windsor, Ontario, Canada.
  • 5. Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada.
  • 6. Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel.
  • 7. Bioinformatics Service Unit and.
  • 8. Bioimaging Unit, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.
  • 9. Montreal Neurological Institute-Hospital and Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
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.

Keywords
Neurodegeneration; Neuroscience; Signal transduction.