A fat to forget: cholesterol dysregulation in Alzheimer’s Disease
Speaker: Jorge Montesinos, PhD. Centro de Investigaciones Biológicas-Margarita Salas
Date: 19th December 12:30h
Lipid abnormalities have long been described in the brain of Alzheimer’s Disease (AD) patients. However, their contribution to pathogenesis remains controversial. In our recent work, we described the dysregulation of mitochondria-associated endoplasmic reticulum membranes (MAMs), a hub for the regulation of cellular lipid homeostasis, as a key event in AD.
We found that, by means of its affinity for cholesterol, Amyloid Precursor Protein-derived C99 accumulates in MAM domains and induces cholesterol trafficking dysregulation. As a result, MAM functionality becomes chronically upregulated while disrupting mitochondrial fitness and lipid homeostasis. Moreover, we defined the cholesterol interactome at MAM in AD cellular models to pinpoint druggable targets and understand the molecular consequences of MAM alteration.
Overall, we present a novel framework for AD pathogenesis that can be linked to the many complex alterations that occur during disease progression, and that may open a door to new therapeutic strategies.