Our Mission

Our laboratory investigates the molecular pathways underlying Alzheimer’s disease. Mutations in the amyloid precursor protein (APP) are causatively linked to Alzheimer’s disease; however, the physiological function of APP remains incompletely understood. APP undergoes proteolytic processing by several enzymes, and we have identified a novel APP- cleaving protease, the rhomboid-related protein 4 (RHBDL4). Importantly, RHBDL4 activity is regulated by cellular cholesterol levels, suggesting a mechanistic link between APP processing and cholesterol, a well-established risk factor for Alzheimer’s disease.

In parallel, apolipoprotein E variant 4 (ApoE4), a key cholesterol transporter, is genetically and causatively associated with Alzheimer’s disease, yet the underlying molecular mechanisms remain unclear. Our research aims are therefore twofold:

(1) To elucidate the physiological function of APP, including its regulation through the RHBDL4-mediated processing pathway. To better understand RHBDL4 regulation, we also investigate other rhomboid proteases of the brain such as RHBDL3

(2) To understand the role of cholesterol in Alzheimer’s disease, with particular focus on ApoE4 and additional cholesterol- transporting proteins such as the cholesteryl ester transport protein (CETP)

To achieve these goals, we employ a multidisciplinary approach combining cell culture systems and mouse models with the extensive support of McGill University’s core facilities. These include mass spectrometry, fluorescence and electron microscopy, histology, flow cytometry, the transgenic animal core, PET imaging, and metabolomics. Ultimately, we seek to translate our mechanistic insights into the development of novel therapeutic strategies aimed at preventing the onset of Alzheimer’s disease.