Duncan Sinclair

Stressful experiences are all around us. These experiences can make us more likely to develop Alzheimer’s disease and, if we have Alzheimer’s disease, can speed up its progression. So it’s vital to understand how stress impacts the brain in Alzheimer’s disease. To understand how stress hormones impact the brain as we age, and especially for people living with Alzheimer’s disease, we have conducted experiments on brain-like cells collected from inside the noses of adult human donors. We have 1) measured levels of more than 4000 proteins (the machinery inside cells) after treatment with dexamethasone, a synthetic stress hormone, 2) measured cell death and proliferation and 3) looked at how an important stress receptor inside cells moves around when triggered by stress hormones. 

Experiments so far have shown us that there are overlapping effects of dexamethasone and amyloid beta (Aβ), a molecule which builds up in the brain in Alzheimer's disease. To our surprise multiple proteins that were dysregulated by Aβ returned to normal levels when also exposed to dexamethasone. These proteins may be promising future therapeutic targets. However, in other ways stress could be damaging. Some proteins that are dysregulated by Aβ were further dysregulated by stress hormones, highlighting ways that stress hormones could make dementia-related problems in the brain worse. Dexamethasone decreased proliferation of brain-like cells, while Aβ increased proliferation. 

Overall, this work is helping us understand how stress and Aβ can work together to shape the brain in older age and Alzheimer’s disease and is suggesting new ways to look for stress-related therapies.

Farnum Z, Mani R, Bindoff A, Wilson R, Fiotakis A, Stephens J, Cho E, Mackay-Sim A, Sinclair D. Convergent effects of synthetic glucocorticoid dexamethasone and amyloid beta in human olfactory neurosphere-derived cells. J Neurochem. 2025 Feb;169(2):e16263. doi: 10.1111/jnc.16263. Epub 2024 Nov 18. PMID: 39556451.

Duncan Sinclair is a researcher and lecturer at the Wicking Dementia Research and Education Centre, University of Tasmania.