NGF controls APP cleavage and insulin signaling in septal neurons: relevance for Alzheimer’s and metabolic diseases

The data presented in this study indicate that NGF downregulates the phosphorylation of APP at the neuron-specific residue T668, does promoting APP-TrkA binding at the expense of the APP-BACE interaction and cleavage and favours APP trafficking to BACE-free neuronal compartments. These data suggest that NGF directly controls the pattern of APP phosphorylation, through TrkA/ShcC signalling pathways, its trafficking and, in part, the APP interactome in forebrain neurons, which ultimately affects APP processing. Thus, novel strategies aimed at stimulating ShcC signalling and/or TrkA-APP binding should be considered as promising therapeutic tools for early neurodegeneration in AD. An interplay between the NGF and insulin signalling systems has been already hypothesized in cultured sympathetic and sensory neurons (Ishii et al., 1985; Recio-Pinto et al., 1986). Recently, it has been shown that IR is activated by phosphorylated TrkA upon NGF activation in PC12 cells (Geetha et al., 2013). In the second part of the study, we showed that cholinergic septal neurons respond to insulin stimulation in vitro. Indeed, NGF is also able to modulate IRs and IRS-1 signalling adaptors in septal neurons further pointing out the mutual modulation of the two pathways in CNS. Moreover, insulin exerts its antiamyloidogenic effect in brain neurons by reducing APP(T668) phosphorylation through a mechanism involving the activation of the NGF receptor. . We developed a novel in vitro model of neuronal insulin resistance mimicking the pattern of insulin activation seen in post-mortem brain AD. Furthermore, we found that NGF improves insulin resistance by stimulating insulin signalling of IRS1 activation and neuronal activity (cFos) in our insulin resistance model. Because insulin has number of roles in the brain, it would be worth studying whether the NGF can promotes other insulin function’s involved in memory, like glucose uptake in neurons.