2022 NCPD Nathaniel Gould

Dr Nathaniel Gould

2022 Post-doctoral Non-clinical Fellowship

Identifying and Manipulating Metabolic Resilience Pathways Contributing to Alzheimer's Disease Predisposition

As we age, our brain has to cope with accumulating environmental, genetic and physiological challenges.
I recently found that an enzyme called quinone reductase 2 (QR2) is involved in the retention of new
memories, and can become harmful later in life. Normally, QR2 is tightly controlled and creates reactive
oxygen species (ROS) that affect brain cell firing properties and memory. However, with age there is a
breakdown in the control of QR2, which becomes over-abundant, and it starts creating too much ROS.
Excess ROS cause damage, as they randomly bind and alter the proteins, fats and DNA that make up our
cells and genes. This damage, called oxidative stress, accumulates as the cells age and is a hallmark of

Our brains ability to cope with such age-related challenges is likely to have some bearing as to whether
or not we remain healthy or live with dementia, and warrants investigation.
One major means by which our brain copes with age-related challenges, is via the molecule RE1-
Silencing Transcription factor (REST). REST appears in the mature brain after middle-age, and is
protective of ageing brain cells. It controls the expression of genes that help brain cells cope, function,
and adapt in response to age-related challenges such as oxidative stress.

Taking skin cells that have been turned to stem cells, donated by people over 70 with or without
dementia, I will create brain cells from these individuals with which to carry out my research.
I aim to evaluate REST, cell physiology and ability to cope with age-related stress, and identify if and how
brain cells of people with dementia fail to cope with age-related stress.
Additionally, I will test a molecule I created to stop QR2, as a potential new drug to help keep brain cells
healthy, and to avoid or delay dementia.


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

Gould N, Scherer G, Silvia Carvalho S et al.

Journal of Clinical Investigation 2023 Oct 2;133(19):e162120. doi: 10.1172/JCI162120. PMID: 37561584; PMCID: PMC10541198.


Ribosome subunits are upregulated in brain samples of a subgroup of individuals with schizophrenia: A systematic gene expression meta-analysis

Ori Mekiten, Assif Yitzhaky, Nathaniel Gould, Kobi Rosenblum, Libi Hertzberg

Journal of Psychiatric Research 2023 Aug;164:372-381. doi: 10.1016/j.jpsychires.2023.06.013. Epub 2023 Jun 30. PMID: 37413782.