Neuroendocrine Pharmacology

Our goal is to understand how hormones shape the female brain metabolism, and why women face a higher burden of neurodegenerative disease.

Women are disproportionately affected by Alzheimer's disease, and the menopause transition reshapes the brain's entire hormonal environment. Understanding why sits at the heart of women's brain health, and at the heart of what we do.

Brain cells run on an enormous energy budget, and mitochondria are what manage it. They are known as the powerhouse of the cell for producing ATP, but they do considerably more, buffering calcium, regulating reactive oxygen species, and holding the switch between a cell's survival and its death. Androgens and estrogens, traditionally filed under reproduction, reach into all of it, and their levels decline across the lifespan. That decline is where we work.

We work in one cell in particular. Neurons get the attention, but they do not handle their own fuel. Astrocytes do. They wrap around the blood vessels, take up glucose as it arrives, hold the only sugar reserve the brain has, and pass fuel on to the neurons that spend it. They also make estrogen themselves and carry receptors for it. So when hormonal support falls away, the astrocyte is where it lands first.

Hormones do not act on cells from a distance. Their receptors have been found inside the mitochondrion itself, which is a useful thing to know when the mitochondrion is what we are trying to protect. Compounds that reach those receptors can hold an astrocyte together through a metabolic crisis that would otherwise kill it, and for some of them we can now say exactly how, down to the shape a molecule makes when it meets its receptor. From there the work runs outward, into signatures we can read in blood and brain, into clinical and population studies, and back again to design compounds that fit better.

Three choices shape how we work. We go down to a single cell, and we measure its energy directly rather than infer it. We run male and female cells side by side, because a difference nobody looks for is a difference nobody finds. And we start from compounds women are already prescribed, because the shortest road from a mechanism to a patient runs through a pharmacy that already stocks it.

Women's brain health has gone under-studied for a long time. We would like to be part of ending that.

Fig. 1- Determinants of brain health and neurodegeneration. Multiple, interacting factors, genetics, epigenetics, ageing, gonadal and brain hormones, metabolism and diet, converge to shape core brain functions such as cognition, plasticity, neurogenesis and neuroprotection, and ultimately the risk of neurodegeneration. Within this landscape, our lab focuses on the role of sex hormones and their crosstalk with metabolism and ageing, to understand the mitochondrial mechanisms driving sex differences in brain vulnerability and to advance women's brain health.