Pedro Belio Mairal thesis defense rehearsal
Abstract :
Alzheimer’s disease (AD) is a neurodegenerative disorder with two major hallmarks: 1)amyloid B (AB) plaques in the brain parenchyma, and 2) neurofibrillary tangles. The recent FDA approval of 3 anti-AB monoclonal antibodies has downplayed some of the existent doubts on the Amyloid hypothesis, but the efficacy of these treatments is limited.
In this context, the precursor of A, C99, is gaining momentum as a neurotoxic factor on its own, and new secretases of the amyloid precursor protein (APP) have been identified. Together, these elements provide new avenues for the study of novel pathological mechanisms and anti-amyloid strategies in AD. Membrane-type 5 matrix metalloproteinase (MT5-MMP) is a recently described APP secretase, cleaving at the n-site. Knockout of MT5-MMP prevented amyloidogenesis and
neuroinflammation in an AD mouse model, and deletion of MT5-MMP transmembrane (TM) and/or intracellular (IC) domains decreased C99 and A levels in human cells. In this thesis, I explored the consequences of MT5-MMP depletion in human neurons and astrocytes and the potential of MT5-MMP TM and IC to modulate C99 and AB levels in an in vitro AD model. In my thesis, I describe an important role of MT5-MMP in dendritic arborization and glial physiology in human neurons and astrocytes. Moreover, I revealed the different roles of MT5-MMP TM and IC in C99 and AB accumulation. Modifications of the MT5-MMP IC changed C99 trafficking, with divergent consequences on C99 and AB levels. Finally, synthetic peptides mimicking certain MT5-MMP IC variants demonstrate the utility of MT5-MMP-based strategies to tackle C99 accumulation.
My PhD thesis expands our knowledge of the roles of specific MT5-MMP domains. Moreover, it provides a framework to exploit the potential of MT5-MMP unique properties for modulating C99 and confirms MT5-MMP as a valuable therapeutic target for preventing amyloidogenesis in AD.
