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 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.

Somatostatin Interneurons of the Insula Mediate QR2-Dependent Novel Taste Memory Enhancement.

Forming long-term memories is crucial for adaptive behavior and survival in changing environments. The molecular consolidation processes which underlie the formation of these long-term memories are dependent on protein synthesis in excitatory and SST-expressing neurons. A centrally important, parallel process to this involves the removal of the memory constraint quinone reductase 2 (QR2), which has been recently shown to enhance memory consolidation for novel experiences in the cortex and hippocampus, via redox modulation. However, it is unknown within which cell type in the cortex removal of QR2 occurs, nor how this affects neuronal function. Here, we use novel taste learning in the mouse anterior insular cortex (aIC) to show that similarly to mRNA translation, QR2 removal occurs in excitatory and SST-expressing neurons. Interestingly, both novel taste and QR2 inhibition reduce excitability specifically within SST, but not excitatory neurons. Furthermore, reducing QR2 expression in SST, but not in PV or excitatory neurons, is sufficient to enhance taste memory. Thus, QR2 mediated intrinsic property changes of SST interneurons in the aIC is a central removable factor to allow novel taste memory formation. This previously unknown involvement of QR2 and SST interneurons in resetting aIC activity hours following learning, describes a molecular mechanism to define cell circuits for novel information. Therefore, the QR2 pathway in SST interneurons provides a fresh new avenue by which to tackle age-related cognitive deficits, while shedding new light onto the functional machinations of long-term memory formation for novel information.

Dopamine-Dependent QR2 Pathway Activation in CA1 Interneurons Enhances Novel Memory Formation.

The formation of memory for a novel experience is a critical cognitive capacity. The ability to form novel memories is sensitive to age-related pathologies and disease, to which prolonged metabolic stress is a major contributing factor. Presently, we describe a dopamine-dependent redox modulation pathway within the hippocampus of male mice that promotes memory consolidation. Namely, following novel information acquisition, quinone reductase 2 (QR2) is suppressed by miRNA-182 (miR-182) in the CA1 region of the hippocampus via dopamine D1 receptor (D1R) activation, a process largely facilitated by locus coeruleus activity. This pathway activation reduces ROS generated by QR2 enzymatic activity, a process that alters the intrinsic properties of CA1 interneurons 3 h following learning, in a form of oxidative eustress. Interestingly, novel experience decreases QR2 expression predominately in inhibitory interneurons. Additionally, we find that in aged animals this newly described QR2 pathway is chronically under activated, resulting in miR-182 underexpression and QR2 overexpression. This leads to accumulative oxidative stress, which can be seen in CA1 via increased levels of oxidized, inactivated potassium channel Kv2.1, which undergoes disulfide bridge oligomerization. This newly described interneuron-specific molecular pathway lies alongside the known mRNA translation-dependent processes necessary for long-term memory formation, entrained by dopamine in CA1. It is a process crucial for the distinguishing features of novel memory, and points to a promising new target for memory enhancement in aging and age-dependent diseases.SIGNIFICANCE STATEMENT One way in which evolution dictates which sensory information will stabilize as an internal representation, relies on information novelty. Dopamine is a central neuromodulator involved in this process in the mammalian hippocampus. Here, we describe for the first time a dopamine D1 receptor-dependent quinone reductase 2 pathway in interneurons. This is a targeted redox event necessary to delineate a novel experience to a robust long-term internal representation. Activation of this pathway alone can explain the effect novelty has on "flashbulb" memories, and it can become dysfunctional with age and diseases, such as Alzheimer's disease.

Muscarinic-Dependent miR-182 and QR2 Expression Regulation in the Anterior Insula Enables Novel Taste Learning.

In a similar manner to other learning paradigms, intact muscarinic acetylcholine receptor (mAChR) neurotransmission or protein synthesis regulation in the anterior insular cortex (aIC) is necessary for appetitive taste learning. Here we describe a parallel local molecular pathway, where GABAA receptor control of mAChR activation causes upregulation of miRNA-182 and quinone reductase 2 (QR2) mRNA destabilization in the rodent aIC. Damage to long-term memory by prevention of this process, with the use of mAChR antagonist scopolamine before novel taste learning, can be rescued by local QR2 inhibition, demonstrating that QR2 acts downstream of local muscarinic activation. Furthermore, we prove for the first time the presence of endogenous QR2 cofactors in the brain, establishing QR2 as a functional reductase there. In turn, we show that QR2 activity causes the generation of reactive oxygen species, leading to modulation in Kv2.1 redox state. QR2 expression reduction therefore is a previously unaccounted mode of mAChR-mediated inflammation reduction, and thus adds QR2 to the cadre of redox modulators in the brain. The concomitant reduction in QR2 activity during memory consolidation suggests a complementary mechanism to the well established molecular processes of this phase, by which the cortex gleans important information from general sensory stimuli. This places QR2 as a promising new target to tackle neurodegenerative inflammation and the associated impediment of novel memory formation in diseases such as Alzheimer's disease.