Ontcijfering van de Moleculaire Bijdragen van Presenilin2/γ-Secretase Complexen aan de Pathogenese van de Ziekte van Alzheimer

Alzheimer's disease (AD) is characterized by the progressive build-up of amyloid-beta (AB) in plaques. gamma-Secretase processing releases AB from the amyloid precursor protein and comes in different flavours because of the existence of two presenilins and APH1 isoforms. Distinct complexes generate slightly different AB profiles and familial AD linked mutations in PSENs shift the production to longer AB species which aggregate more easily. PSEN1/gamma-secretase is broadly distributed in neurons, whereas PSEN2/gamma-secretase is restricted to late endosomes/lysosomes where it majorly produces the pathological relevant intracellular AB pool. Unexpectedly, PSEN2 deficiency results in higher AB production and increased plaque load in a transgenic AD model pointing to a potential protective role of PSEN2 in AD pathology. I postulate that in normal, healthy conditions, part of APP is processed via PSEN2/gamma-secretase providing a clearance pathway for AB accumulation as long as lysosomes are intact. In PSEN2 deficiency, all APP is processed through PSEN1/gamma-secretase resulting in increased AB secretion and plaque formation. We further predict that in case of FAD-PSEN2 mutations, intracellular toxic AB is strongly promoted leading to its aggregation and ultimately lysosomal dysfunction/damage. To test this hypothesis I will develop new PSEN2-targeted AD models and evaluate in vivo, and including cellular models derived from these models, AD pathology, AB profiles and lysosomal function