Pathological convergence of APP and SNCA deficiency in hippocampal degeneration of young rats.

The common pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD) has been supported by biochemical, genetic and molecular evidence. Mitochondrial dysfunction is considered to be the common pathology in early AD and PD. The physiological regulation of APP and α-synuclein on mitochondria remains unclear, let alone whether they share common regulatory mechanisms affecting the development of neurodegenerative diseases. By studying gene knockout rats, the commonality of physiological APP and α-synuclein in maintaining mitochondrial function through calcium homeostasis regulation was revealed, which was critical in inhibiting hippocampal degeneration in young rats. APP and α-synuclein both control hippocampal mitochondrial calcium intake and outflow. In the mitochondrial calcium influx regulation, APP and α-synuclein are located on the mitochondrial-associated endoplasmic reticulum membrane (MAM) and converge to regulate the IPR1-Grp75-VDAC2 axis. Mitochondrial calcium outflow is redundantly promoted by both α-synuclein and APP. Loss of APP or SNCA leads to mitochondrial calcium overload, thus enhancing aerobic respiration and ER stress, and ultimately causing excessive apoptosis in the hippocampus and spatial memory impairment in young rats. Based on this study, we believe that the physiological function impairment of APP and SNCA is the early core pathology to induce mitochondrial dysfunction at the early stage of AD and PD, while the IPR1-Grp75-VDAC2 axis might be the common drug target of these two diseases.