Presequence protease reverses mitochondria-specific amyloid-ß-induced mitophagy to protect mitochondria.

ABSTRACT

Amyloid-ß (Aß) peptide is accumulated in the mitochondria and has been shown to play a central role in the development of Alzheimer's disease (AD). It has been shown that exposure of neurons to aggregated Aß can result in damaged mitochondria and dysregulated mitophagy, indicating that changes in the Aß content of mitochondria may affect the levels of mitophagy and interfere with the progression of AD. However, the direct influence of mitochondrial Aß on mitophagy has not been elucidated. In the present study, the effect of the mitochondria-specific Aß was assessed following a direct change of Aß content in the mitochondria. We directly change mitochondrial Aß by transfecting cells with mitochondria-associated plasmids, including the mitochondrial outer membrane protein translocase 22 (TOMM22) and 40 (TOMM40) or presequence protease (PreP) overexpression plasmids. The changes in the levels of mitophagy were assessed by TEM, Western blot, mito-Keima construct, organelle tracker, and probe JC-1 assay. We demonstrated that increased mitochondrial Aß content enhance mitophagy levels; overexpression of PreP could reverse the mitochondrial Aß-induced mitophagy levels in vivo and in vitro by reversing the levels of reactive oxygen species (ROS) and the mitochondrial membrane potential. The data provide novel insight into the role of mitochondria-specific Aß in the progression of AD pathophysiology.