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

Abstract

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.

Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System

“…During the critical period, lesions such as contralateral eye monocular enucleation or restricted lesion to the contralateral retina trigger a series of adaptive responses of the visual system [31, 32]. In rodents, monocular enucleation leads to a massive deafferentation of subcortical visual targets of retinal axons, the dorsal lateral geniculate nucleus and superior colliculus, resulting in a remarkable plastic response of intact axons originating in the remaining eye with extensive sprouting over denervated territories [33] (Fig.…”

“…Also, adrenergic sprouting was attenuated in IL-6 KO mice in a model of spinal nerve lesion [52]. In the monocular enucleation model, Vasques et al[32], brought evidence that α-secretase activity is important for the axonal sprouting of ipsilateral retinocollicular projections from the intact eye, by favoring the production of sAPPα. Furthermore, it has been described that the proinflammatory cytokine IL-1β enhances α-cleavage of APP, upregulating sAPPα content in vitro [53].…”

Signaling pathways modulated by monocular enucleation in the superior colliculus of juvenile rats

“…In a recent report, our group demonstrated that ME performed at PND 10, within the critical period of retinocollicular circuitry development, induces a robust arborization and expansion of ipsilateral projections as soon as 24 hr after lesion (Chagas et al., 2019). Several proteins levels are modulated by ME, such as growth‐associated protein‐43 (GAP‐43), related to axonal growth (Mendonça et al., 2010); the nuclear transcription factor kappa‐B, which regulates the expression of several genes in the nervous system (Hernandes et al., 2012); the cAMP response element‐binding protein (CREB), which plays an important role in neuronal plasticity (Vierci et al., 2013); the soluble α‐APP, a product of amyloid precursor protein (APP) cleavage related to axonal growth and synaptogenesis (Vasques et al., 2017), among others. However, it is not yet fully understood which are the main signaling pathways responsible for the intense axonal reorganization observed in this model.…”

The genes associated with early-onset Alzheimer’s disease

“…APP is essential for physiological processes such as neural proliferation, migration, differentiation, plasticity and synaptogenesis [ 32 – 36 ]. Acutely knock down APP in the developing cortex of Sprague Dawley rats revealed that neuronal precursor cells in the embryonic cortex require APP to migrate correctly into the nascent cortical plate [ 32 ].…”

“…sAPPα was secreted in the early stages of differentiation (neuronal progenitors), and sAPPβ was usually secreted after the production of deep-layer neurons. A recent study has shown that sAPPα, a neurotrophic fragment released from the metabolites of APP, is also important to synaptogenesis [ 36 , 48 ].…”