Apr 22, 2024
The phospholipase D pathway in brain functioning and Alzheimer’s disease
Lipids are a major constituent of the brain and have been implicated as key mediators of
Alzheimer's disease (AD) pathogenesis. Recent advances in mass-spectrometry lipidomics
showed that specific lipid signaling pathways are diDerentially regulated in particular
physiological and disease states. The hippocampus is a brain structure relevant for learning and memory and is impaired in AD. In an unbiased lipidomic study, we compared the lipid composition along its longitudinal axis, and among many relevant lipid hits, we showed a phosphatidic acid gradient, with higher levels in the dorsal hippocampus. At the pathological level, we had also shown that amyloid beta increased the activity of the lipid-modulating enzyme, phospholipase D (PLD), in diDerent brain cell types. In mammals there are two main canonical PLDs, PLD1 and PLD2, and both convert phosphatidylcholine into phosphatidic acid. We also previously showed that the ablation of PLD2 in an amyloidogenesis model had a protective eDect at the synaptic and behavioral levels and that the ablation of PLD1 impaired the functioning of the hippocampus along its longitudinal axis. We are now focused in understanding the mechanism of protection conferred by PLD2 ablation in AD, and the brain detrimental eDects caused by PLD1
ablation. Since PLD1 gene variants have been linked to brain magnetic resonance imaging
phenotypic signatures, we are further exploring the relevance of these signatures in AD
populations.
Summary and research interests:
I was a student in the joint MD/PhD program of the University of Minho, Portugal and Columbia University, NYC, USA. I carried out my PhD studies at Columbia University, between 2007 and 2010, under the supervision of Gilbert Di Paolo and Nuno Sousa, and my MD studies at University of Minho. While studying the role of lipid signaling in Alzheimer’s disease pathogenesis, I showed that the ablation of the lipid-modulating enzyme, phospholipase D2, was protective in different Alzheimer’s disease models. Following my MD/PhD, in 2011 I started my own laboratory as an Assistant Professor at the School of Medicine, University of Minho. I have expanded my research interests to the study of mood disorders. Using an unbiased lipidomic approach, my laboratory showed that specific lipid signaling pathways were altered in a chronic stress model, unraveling new potential therapeutic targets. In parallel with my academic work I continued my medical career. I am currently a Neuroradiologist at Hospital de Braga and I am now using lipidomic approaches together with brain imaging to study neurodegenerative disorders.