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 9

Drinking YB-537 for 4 months significantly reduces brain pathologies associated with dementia in the brains of 9-month-old 5xFAD male mice.

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Drinking YB-537 for 4 months significantly reduces brain pathologies ass...
(A) 4-HNE is unchanged in the hippocampus (1-way ANOVA, P = 0.1926), but is significantly reduced in the cortex (1-way ANOVA, P = 0.0009; Tukey’s multiple comparison, YB-537 versus vehicle, P = 0.0070; YB-537 versus WT, P = 0.3029; vehicle versus WT, P = 0.0013) of 9-month-old male 5xFAD mice following 4-months of YB-537 consumption in drinking water. (B) Amyloid β is reduced in the hippocampus (Kruskal-Wallis test, P < 0.0001; Dunn’s multiple comparison, vehicle versus WT, P = 0.0013; vehicle versus YB-537, P = 0.0535; WT versus YB-537, P = 0.2789), and significantly reduced in the cortex (Kruskal-Wallis test, P = 0.0003; Dunn’s multiple comparison, vehicle versus WT, P = 0.0563; vehicle versus YB-537, P = 0.0026; WT versus YB-537, P > 0.9999) of 9-month-old male 5xFAD mice, following 4-months of YB-537 consumption in drinking water. (C) p-tau is unchanged in the hippocampus (1-way ANOVA, P = 0.4520) and the cortex (1-way ANOVA, P = 0.9557) of 9-month-old male 5xFAD mice, following 4-months of YB-537 consumption in drinking water. (D) Iba1 is reduced in the hippocampus (Kruskal-Wallis test, P = 0.0011; Dunn’s multiple comparison, vehicle versus WT, P = 0.0058; vehicle versus YB-537, P = 0.0512; WT versus YB-537, P = 0.6510), and significantly reduced in the cortex (Kruskal-Wallis test, P < 0.0001; Dunn’s multiple comparison, vehicle versus WT, P = 0.6638; vehicle versus YB-537, P = 0.0008; WT versus YB-537, P = 0.2284) of 9-month-old male 5xFAD mice, following 4 months of YB-537 consumption in drinking water. (E) GFAP is insignificantly reduced in the hippocampus (1-way ANOVA, P = 0.0589), and significantly reduced in the cortex (Kruskal-Wallis test, P = 0.0116; Dunn’s multiple comparison, vehicle versus WT, P = 0.1450; vehicle versus YB-537, P = 0.0215; WT versus YB-537, P > 0.9999) of 9-month-old male 5xFAD mice, following 4 months of YB-537 consumption in drinking water. n for all experiments: YB-537, 9; vehicle, 7; WT, 4. Data are shown as mean ± SEM. *P < 0.05; **P < 0.005; ***P < 0.0005. Scale bars: 50 μm.