Monocular denervation of visual nuclei modulates APP processing and sAPPα production: A possible role on neural plasticity

Amyloid precursor protein (APP) is essential to physiological processes such as synapse formation and neural plasticity. Sequential proteolysis of APP by beta- and gamma-secretases generates amyloid-beta peptide (Aβ), the main component of senile plaques in Alzheimer Disease. Alternative APP cleavage by alpha-secretase occurs within Aβ domain, releasing soluble α-APP (sAPPα), a neurotrophic fragment. Among other functions, sAPPα is important to synaptogenesis, neural survival and axonal growth. APP and sAPPα levels are increased in models of neuroplasticity, which suggests an important role for APP and its metabolites, especially sAPPα, in the rearranging brain. In this work we analyzed the effects of monocular enucleation (ME), a classical model of lesion-induced plasticity, upon APP content, processing and also in secretases levels. Besides, we addressed whether α-secretase activity is crucial for retinotectal remodeling after ME. Our results showed that ME induced a transient reduction in total APP content. We also detected an increase in α-secretase expression and in sAPP production concomitant with a reduction in Aβ and β-secretase contents. These data suggest that ME facilitates APP processing by the non-amyloidogenic pathway, increasing sAPPα levels. Indeed, the pharmacological inhibition of α-secretase activity reduced the axonal sprouting of ipsilateral retinocollicular projections from the intact eye after ME, suggesting that sAPPα is necessary for synaptic structural rearrangement. Understanding how APP processing is regulated under lesion conditions may provide new insights into APP physiological role on neural plasticity.