Alexandra Grubman

Despite intensive research into Alzheimer’s disease, we still have no cure. Recent studies show a strong genetic association of late onset Alzheimer’s disease to microglia, a critical cell type in the brain essential for proper functioning of nerve cells and removing damage in the brain. We discovered two types of microglia in the brains of mice modelling Alzheimer’s disease. Our data unveiled that one type of microglia protects the brain by removing damage associated with Alzheimer’s, whereas the other show a prematurely aging identity.

This project examined the genes turned on in individual cells in post-mortem brains donated by patients with Alzheimer’s disease and found in human brains a type of microglia similar to the plaque-eating microglia in mouse brains. We also found similarities in the functional roles between mouse and human Alzheimer’s microglia in terms of the ability to eat up synapses, the connections between neurons.

We next tested whether our predicted drugs that can switch microglia into the protective plaque-eating type. We found that using our drugs we can control a group of genes, and importantly the functions, in microglia-like cells made from human stem-cells. We have started to test directly the involvement of the molecule HIF1 in controlling the microglial switch in mice modelling Alzheimer’s disease.

Grubman, A., Chew, G., Ouyang, J.F., Sun, G., Choo, X.Y., McLean, C., Simmons, R.K., Buckberry, S., Vargas-Landin, D.B., Poppe, D., Pflueger, J., Lister, R., Rackham, O.J.L., Petretto, E., & Polo, J.M., 2019 A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation Nature Neuroscience volume 22, pp 2087–2097 DOI: 10.1038/s41593-019-0539-4

Grubman, A., Choo, X.Y., Chew, G. et al. Transcriptional signature in microglia associated with Aβ plaque phagocytosis. Nat Commun 12, 3015 (2021). https://doi.org/10.1038/s41467-021-23111-1

At the time of award, Dr Grubman was a National Health and Medical Research Council – Australian Research Council Dementia Research Development Fellow in the lab of Jose Polo at the Australian Regenerative Medicine Institute and Biomedicine Discovery Institute at Monash University.

Dr Grubman is currently a medical advisor working on Alzheimer's disease at Eisai Australia.