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

Nathaniel L. Gould, Gila R. Scherer, Silvia Carvalho, Khriesto Shurrush, Haneen Kayyal, Efrat Edry, Alina Elkobi, Orit David, Maria Foqara, Darshit Thakar, Tommaso Pavesi, Vijendra Sharma, Matthew Walker, Matthew Maitland, Orly Dym, Shira Albeck, Yoav Peleg, Nicolas Germain, Ilana Babaev, Haleli SharirMaya Lalzar, Boris Shklyar, Neta Hazut, Mohammad Khamaisy, Maxime Lévesque, Gilles Lajoie, Massimo Avoli, Gabriel Amitai, Bruce Lefker, Chakrapani Subramanyam, Brian Shilton, Haim Barr, Kobi Rosenblum

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish
Article numbere162120
JournalJournal of Clinical Investigation
Volume133
Issue number19
DOIs
StatePublished - 2 Oct 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 Gould et al.

Funding

Special thanks to all Rosenblum lab members, Dan Frenkel and Shani Kanfi from Tel-Aviv University, Dorit Farfara from the Tech-nion, to the veterinary and technical staff at the University of Hai-fa, and to Nahum Sonenberg. The current work was supported by Israeli Science Foundation No. 258/20 and 946/17 and Morasha for bio-medical research 604/15 to KR. NLG is a recipient of the University of Haifa President Fellowship for Excellent Ph.D. students. GRS is a recipient of a research grant from The Center for Integration in Science, of the Ministry of Aliya and Integration. HK is a recipient of the Edmond de Rothschild’s scholarship. Special thanks to all Rosenblum lab members, Dan Frenkel and Shani Kanfi from Tel-Aviv University, Dorit Farfara from the Tech-nion, to the veterinary and technical staff at the University of Haifa, and to Nahum Sonenberg. The current work was supported by Israeli Science Foundation No. 258/20 and 946/17 and Morasha for bio-medical research 604/15 to KR. NLG is a recipient of the University of Haifa President Fellowship for Excellent Ph.D. students. GRS is a recipient of a research grant from The Center for Integration in Science, of the Ministry of Aliya and Integration. HK is a recipient of the Edmond de Rothschild’s scholarship.

FundersFunder number
University of Hai-fa
Israel Science Foundation946/17, 604/15, 258/20
Tel Aviv University
University of Haifa

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