Role of presenilins in autophagy and growth factor signaling

Abstract

Alzheimer's disease is the most common neurodegenerative disease and affects millions of people worldwide. To date, no efficient therapies are known for a cure. As people suffering from diabetes mellitus type 2 have an increased risk to develop AD and PS proteins affect autophagy, this study combines these characteristics by further evaluating how γ-secretase/PS proteins affects the autophagy-, insulin- and IGF1-related PI3K/Akt/mTOR signaling pathway. <br /> For that, differentiated SH-SY5Y- and PS-deficient MEF cells were treated with DAPT for pharmacological inhibition of the γ-secretase, as well as starvation medium, insulin or IGF1 for induction of the PI3K/Akt/mTOR signaling pathway. Furthermore, additional pharmacological treatments using rapamycin, bafilomycin A1, 3-MA and chloroquine were performed for further modulations of the pathway. <br /> This study indicates that starvation-induced autophagy affects subcellular distributions of PS proteins as well as subcellular distributions and expression of IGF-R and I-R. Furthermore, PS-deficiency leads to impaired autophagic clearance, lysosomal accumulation and highly impaired phosphorylation of Akt. Most interestingly, impaired autophagic clearance in PS-deficient cells can be highly improved by insulin- and IGF1 treatment. Moreover, the results indicate that all observed dysfunctions depend on PS-expression in a γ-secretase activity- independent manner and most probably independent of Aß generation. <br /> This study successfully demonstrates that PS-deficient cells show a highly impaired adaptation to environmental stress, which might subsequently lead to apoptosis and neurodegeneration independent of Aß generation and γ-secretase activity. However, the exact mechanisms on how PS proteins interact with the PI3K/Akt/mTOR signaling pathway independently of their catalytic activity need to be further elucidated. Moreover, it is still unclear, whether increased autophagic clearance induced by insulin- and IGF1 treatment in PS-deficient cells leads to an improvement of their cellular homoeostasis. Independent of the most preferably pharmacologically targeted Aβ, hyperphosphorylated tau and γ-secretase itself, this study highly indicates the PI3K/Akt/mTOR signaling pathway to be an important target for a possible pharmacological treatment of AD.