Role y-secretase heterogeneity in intracellular AB production, lysosomal toxicity, and pathogenesis: contribution of familial Alzheimer’s disease mutations in presenilins and late onset Alzheimer’s disease risk factors

Alzheimer’s disease (AD) is characterized by amyloid β (Aβ) plaques and tangles. These hallmarks appear relatively late in disease stirring the debate whether they are a consequence of earlier pathogenic processes. Herein intracellular Aβ accumulation precede their formation, and correlates better with synaptic dysfunction and cognitive decline. Our recent data suggest that the composition of Aβ yielding γ-secretase complexes plays a role in this phenomenon. Here, presenilin 2 (PSEN2) assemblies, unlike those of PSEN1, more prominently affect intracellular Aβ production. Ongoing experiments also imply that PSEN2 expression is under control of PSEN1, suggesting an intriguing molecular crosstalk that could keep the levels of intracellular Aβ in check. Thus, factors that distort the subcellular localization of PSEN2-complexes and/or expression may affect the internal Aβ pool. In this project we aim to:

1.  identify key regulators involved in PSEN1 control of PSEN2 levels and
2. test if these are influenced by familial AD mutations.
3. Furthermore, we will test if PSEN2 localization/levels are affected by altered expression of late onset AD risk genes. This knowledge will be tested in engineered differentiated neurons on lysosome function in turnover and degradation. These complementary approaches may provide further insights into mechanisms that underlie intracellular Aβ pile up and deepen our understanding of processes that govern early stages of AD.