Mécanismes de régulation de l'activité de la protease "rhomboid-like-4" et de sa stimulation dans la prévention de l'Aβ

 

Lisa Münter

Université McGill

 

Domaine : neurosciences, santé mentale et toxicomanies

Fonds d'innovation Pfizer-FRQS sur la maladie d'Alzheimer - volet 2

Concours 2015-2016

Alzheimer disease is the most common form of dementia and currently affects more than 20 million people worldwide. The first molecular changes indicative of Alzheimer disease occur as early as 15 – 30 years before the onset of clinical symptoms. Thus, strategies that prevent disease progression at early, pre-symptomatic stages will likely be the most effective. One of the early molecular markers are amyloid-beta peptides, which are toxic to neurons of the brain and cause cell death. Amyloid-beta peptides are cut out from a larger ‘amyloid precursor protein' (APP) by two different enzymes, a cellular pathway termed amyloidogenic APP processing.

Now, we observed a new APP processing pathway through a recently discovered enzyme not previously known to influence Alzheimer disease, which is the so called rhomboid protease 4. Rhomboid protease 4 efficiently cleaves APP inside the cell and thus bypasses APP from amyloidogenic processing in which toxic amyloid-beta peptides are usually generated. Consequently, when APP is cleaved by rhomboid, very few amyloid-beta peptides are produced indicating that rhomboid-mediated APP processing is a protective pathway. Rhomboid protease 4 is increased in the brains of Alzheimer patients as compared to age-matched controls implying that the increase in rhomboid protein levels may be an adaptive response to the cell stress and amyloid-beta peptide toxicity occurring the Alzheimer disease brain. In this project, we will investigate in detail the molecular mechanisms that drive APP into the rhomboid-protease processing pathway. In the long term, the activation of this pathway may be a strategy to prevent Alzheimer disease.