Rosenblum Lab Molecular and Cellular Mechanisms Underlying Learning and Memory

    Memory constraints and enhancers

    Memory enhancement based on enhancement of mRNA translation are described at length here and here. While most of our research thus far has focused on the dependence of long term memory on a complex array of mRNA and protein synthesis that occurs within relevant cells in the brain and key molecules involved in this process of memory consolidation, in a recent study, uniquely, we have identified a constraint on memory formation in the mammalian brain, namely the quinone reductase 2 enzyme (QR2).

    We have found that QR2 acts as a constraint until it is removed by neuromodulators such as acetylcholine and dopamine, which are released in the brain by novel information. These neuromodulators are slowly lost during ageing, and are more acutely damaged in neurodegenerative diseases such as Alzheimer’s and Parkinson’s (AD and PD, respectively). The persistence of new memories and novel information are severely damaged as a result, and QR2 has also been found in elevated levels in post mortem brain samples of AD and PD patients. However, we have shown that removing QR2 from rodent models of dementia (both in aged animals and others that bear familial Alzheimer’s genes) corrects their memory and cognition (Rappaport et al. 2015).

    NQO2 is related to another enzyme, NQO1, which clears away harmful reactive oxygen species (ROS; the cause of oxidative stress, a major research direction in neurodegenerative disease research) from cells, preventing oxidative stress that may lead to cell death. Not much is known about QR2, and we are actively searching for what it does in the brain. However, it has been shown that QR2 acts very quickly on a kind of quinone that NQO1 acts on much more slowly. This leads to an accumulation of this quinone in an unstable form that ends up generating more ROS in the cells. Rather than preventing oxidative stress, QR2 causes it. We have a provisional patent on QR2 as a target for memory enhancement (US application number 15/126,291). Currently we aim to better understand signaling cascades upstream and downstream to QR2 and its function in different brain structures (Gould et al., in preparation)

    References

    Rappaport AN, Jacob E, Sharma V, Inberg S, Elkobi A, Ounallah-Saad H, Pasmanik-Chor M, Edry E, Rosenblum K. 2015. Expression of quinone reductase-2 in the cortex is a muscarinic acetylcholine receptor-dependent memory consolidation constraint. J Neurosci 35: 15568-15581.

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