Let’s not forget: Peptidases in Alzheimer’s disease

In this thesis, we investigated the role of peptidases in Alzheimer’s disease (AD). AD is characterized by extracellular aggregates consisting of amyloid-β (Aβ) peptides and accumulation of these peptides starts decades before the onset of the first symptoms. We described which peptidases degrade the Aβ peptide and how their levels and activity change during the progression of AD. We show that in presymptomatic stages of AD Aβ degradation is already decreased. We suggest that especially the diminished levels of IDE contribute to less efficient Aβ degradation in these stages and that it may initiate Aβ accumulation, plaque formation and the progression to AD. Furthermore, we investigated whether changes in peptidase activity in presymptomatic stages of AD can be used to diagnose the disease. We showed that measuring Aβ degradation rates in ante mortem CSF may become a diagnostic tool, but only in combination with other biomarkers. Furthermore, TPP2 activity affects APP levels, processing and trafficking and we suggest a role for TPP2 in AD. This thesis contributes to a better understanding of the role of peptidases in neurodegenerative disease, and we show that these peptidases are important players in the initiation and progression of AD. Understanding of the processes involved in presymptomatic stages may allow for therapeutic intervention before the disease becomes manifest.