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 Sharir, Maya 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
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 Sharir, Maya 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
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Research Article Neuroscience

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

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.

Authors

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 Sharir, Maya 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

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Figure 1

QR2 KO in a human cell line induces functional proteomic changes antagonistic to that of the cortex of patients with Alzheimer’s disease.

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QR2 KO in a human cell line induces functional proteomic changes antagon...
(A) Two independent QR2Δ HCT cell lines (C3 and C5) show similar patterns of changes in protein expression compared with control cell lines (NS) with significant correlation (Pearson r = 0.83, P < 0.0001). (B) Overlap between differentially expressed proteins from the current study and from DLPFC tissues of patients with AD compared with controls, reported in Johnson et al., (20). Left: Venn diagram presenting numbers of overlapping proteins. Middle: Significance of enrichment of 4 functional categories representing contrasting effects of QR2 KO and AD. Right: z-score and enrichment significance for the same 4 functional categories within each of the QR2Δ cell lines and AD sets separately. Enrichment was considered significant for FDR adjusted P value <0.05. (C) QR2 KO in HCT116 cells significantly lowers baseline ROS levels (n = 5 per group; unpaired t test, P = 0.0078). (D) Ablation of QR2 in QR2Δ HCT116 confirm QR2 KO (n = 6 per group; unpaired t test, P = 0.0019). (E) QR2 KO significantly increases NDUFA9 levels (n = 6 per group; unpaired t test, P = 0.0055). (F) QR2 KO significantly increases CD73 levels (n = 6 per group; unpaired t test, P = 0.0012). (G) Immunoblot images of QR2, NDUFA9, CD73, and tubulin from QR2Δ HCT116 cells and isogenic controls. Unless stated otherwise, data are shown as mean ± SEM; **P < 0.01; ***P < 0.001.