APP Genetic Deficiency Alters Intracellular Ca Homeostasis and Delays Axonal Degeneration in Dorsal Root Ganglion Sensory Neurons.

The activation of self-destructive cellular programs helps sculpt the nervous system during development, but the molecular mechanisms used are not fully understood. Prior studies have investigated the role of the APP in the developmental degeneration of sensory neurons with contradictory results. In this work, we sought to elucidate the impact of APP deletion in the development of the sensory nervous system and Our data show an increase in the number of sciatic nerve axons in adult male and female mice, consistent with the hypothesis that APP plays a pro-degenerative role in the development of peripheral axons. , we show that genetic deletion of APP delays axonal degeneration triggered by nerve growth factor deprivation, indicating that APP does play a pro-degenerative role. Interestingly, APP depletion does not affect caspase-3 levels but significantly attenuates the rise of axoplasmic Ca that occurs during degeneration. We examined intracellular Ca mechanisms that could be involved and found that DRG neurons had increased Ca levels within the endoplasmic reticulum and enhanced store-operated Ca entry. We also observed that DRG axons lacking APP have more mitochondria than their WT counterparts, but these display a lower mitochondrial membrane potential. Finally, we present evidence that APP deficiency causes an increase in mitochondrial Ca buffering capacity. Our results support the hypothesis that APP plays a pro-degenerative role in the developmental degeneration of DRG sensory neurons, and unveil the importance of APP in the regulation of calcium signaling in sensory neurons. The nervous system goes through a phase of pruning and programmed neuronal cell death during development to reach maturity. In such context, the role played by the APP in the peripheral nervous system has been controversial, ranging from pro-survival to pro-degenerative. Here we present evidence and supporting the pro-degenerative role of APP, demonstrating the ability of APP to alter intracellular Ca homeostasis and mitochondria, critical players of programmed cell death. This work provides a better understanding of the physiological function of APP and its implication in developmental neuronal death in the nervous system.