Endosomal trafficking defects and Alzheimer's Disease
Neuronal Trafficking in Aging Campus, Sant'Ana Pólo de Investigação, NOVA Medical School, Lisbon
The causal mechanisms of late-onset Alzheimer's disease (LOAD), the most common form of AD, remain unclear. AD is a neurodegenerative disease that impairs memory. Early-onset familial AD (eFAD) is rare and caused by mutations in amyloid precursor protein (APP) or presenilins (γ-cleavage of APP) that lead to excessive neuronal production of the longest form of beta-amyloid (Aβ42). Aβ42 is produced intracellularly upon APP processing in endosomes and controlled by the trafficking of APP and its secretases. Endosomal trafficking dysfunction has been suggested as a putative causal mechanism of LOAD. We are investigating the mechanisms whereby two genetic risk factors, BIN1 and CD2AP, regulators of endocytic trafficking and actin dynamics, increase the risk of developing AD. We have recently discovered that Bin1 and CD2AP loss of function increase Aβ42 endocytic production by specific and polarized mechanisms in neurons. We are currently investigating how Bin1 and CD2AP controls endosomal amyloid production and its impact on synapses. We expect to determine the contribution of endosomal trafficking defects in the development of LOAD in individuals carrying variants in Bin1 and CD2AP.
Host: Estibaliz Capetillo