β-Amyloid Precursor Protein Intracellular Domain Controls Mitochondrial Function by Modulating Phosphatase and Tensin Homolog–Induced Kinase 1 Transcription in Cells and in Alzheimer Mice Models

Abstract Background Mitophagy and mitochondrial dynamics alterations are two major hallmarks of neurodegenerative diseases. Dysfunctional mitochondria accumulate in Alzheimer's disease-affected brains by yet unexplained mechanisms. Methods We combined cell biology, molecular biology and pharmacological approaches to unravel a novel molecular pathway by which presenilins control Pink-1 expression and transcription. In vivo approaches were carried out on various transgenic and knockout animals as well as in AAV-infected mice. Functional read-out and mitochondrial physiology (mitochondrial potential, Δψmit) were assessed by combined procedures including Flow cytometry, live imaging analysis and immunohistochemistry. Results We show that presenilins 1 and 2 trigger opposite effects on promoter transactivation, mRNA and protein expression of PTEN-induced kinase 1 (Pink-1). This control is linked to γ-secretase activity and βAPP but independent of PTEN. We show that APP Intracellular Domain (AICD) accounts for presenilin-dependent phenotype and up-regulates Pink-1 transactivation in cells as well as in vivo in a FOXO3a-dependent manner. Interestingly, the modulation of γ-secretase activity or AICD expression impacts Pink-1-related control of mitophagy and mitochondrial dynamics. Finally, we show that parkin acts upstream of presenilins to control Pink-1 promoter transactivation and protein expression. Conclusions Overall, we delineate a molecular cascade presenilins-AICD-FOXO3a linking Parkin to Pink-1. Our study demonstrates an AICD-mediated Pink-1-dependent control of mitochondrial physiology by presenilins. Furthermore, it unravels a parkin-Pink-1 feedback loop controlling mitochondrial physiology that could be disrupted in neurodegenerative conditions.