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

Juliana Ferreira Vasques1, Pedro Vinícius Bastos Heringer1, Renata Guedes de Jesus Gonçalves1, Paula Campello-Costa1, Claudio Alberto Serfaty1, Adriana da Cunha Faria-Melibeu1
1Programa de Neurociências, Departamento de Neurobiologia, Instituto de Biologia, Universidade Federal Fluminense, CEP 24001-970, Niterói 100180, RJ, Brazil

Tóm tắt

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.


Tài liệu tham khảo

10.1038/srep11708 10.1016/j.neurobiolaging.2006.11.004 10.1016/0003-2697(76)90527-3 10.1038/85064 10.1371/journal.pone.0016301 Cheng G., 2002, Phosphatidylinositol‐3‐kinase‐Akt‐kinase and p42/p44 mitogen‐activated protein kinases mediate neurotrophic and excitoprotective actions of a secreted form of amyloid precursor protein, Exp. Neuro., 175, 407, 10.1006/exnr.2002.7920 Cline H., 1990, NMDA receptor agonist and antagonists alter retinal ganglion cell arbor structure in the developing frog retinotectal projection, J. Neurosci., 10, 1197, 10.1523/JNEUROSCI.10-04-01197.1990 10.1007/BF03402076 10.1016/j.mcn.2010.04.007 Del Prete D., 2014, APP is cleaved by Bace1 in pre‐synaptic vesicles and establishes a pre‐synaptic interactome, via its intracellular domain, with molecular complexes that regulate pre‐synaptic vesicles functions, PLoS ONE, 9, e108576, 10.1371/journal.pone.0108576 10.1371/journal.pone.0084962 10.1111/j.1460-9568.2008.06398.x 10.1002/cne.901900402 10.1016/j.neuroscience.2015.11.031 10.1016/j.conb.2012.02.002 10.1016/j.neurobiolaging.2005.10.020 10.1007/s00401-014-1368-x 10.1111/j.1755-5949.2010.00221.x 10.1016/j.neuron.2007.10.003 10.1097/00001756-199707070-00009 Jorissen E., 2010, The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex, J. Neurosci., 30, 4833, 10.1523/JNEUROSCI.5221-09.2010 Kang E.B., 2014, Effects of treadmill exercise on brain insulin signaling and β‐amyloid in intracerebroventricular streptozotocin induced‐memory impairment in rats, J. Exerc. Nutrition Biochem., 18, 89, 10.5717/jenb.2014.18.1.89 10.1038/325733a0 10.1038/sj.emboj.7600757 10.1002/cne.902180304 10.1002/cne.901890407 10.1046/j.1365-2710.2002.00415.x 10.1523/JNEUROSCI.1984-10.2010 10.1016/j.neulet.2010.04.027 Mesulam M.M., 1978, Tetramethyl benzidine for horseradish peroxidase neurohistochemistry: a non‐carcinogenic blue reaction product with superior sensitivity for visualizing neural afferents and efferents, J. Histochem. Cytochem., 26, 106, 10.1177/26.2.24068 10.1038/cddis.2014.352 10.1111/j.1471-4159.1993.tb02147.x 10.1101/cshperspect.a006288 Musardo S., 2013, Trafficking in neurons: searching for new targets for Alzheimer's disease future therapies, Eur. J. Pharmacol., 719, 84, 10.1016/j.ejphar.2013.07.019 Nikolaev A., 2009, APP binds DR6 to trigger axon pruning and neuron death via distinct caspases, Nature, 7232, 981, 10.1038/nature07767 10.1159/000110638 Paudel S., 2013, ADAM10 mediates N‐cadherin ectodomain shedding during retinal ganglion cell differentiation in primary cultured retinal cells from the developing chick retina, J. Cell Biochem., 114, 942, 10.1002/jcb.24435 10.1523/JNEUROSCI.5910-12.2013 10.1002/cne.902500103 10.1523/JNEUROSCI.1026-07.2007 10.1073/pnas.91.16.7450 Rybnikova E., 2002, Developmental regulation and neuronal expression of the cellular disintegrin ADAM11 gene in mouse nervous system, Neuroscience, 112, 921, 10.1016/S0306-4522(02)00124-0 10.1152/physrev.00012.2013 10.1016/j.bbr.2008.02.016 10.1016/j.brainresbull.2005.04.005 Slack B.E., 2001, Constitutive shedding of the amyloid precursor protein ectodomain is up‐regulated by tumor necrosis factor‐alpha converting enzyme, J. Biochem., 357, 787, 10.1042/bj3570787 10.1016/0165-0270(95)00014-L 10.1371/journal.pone.0034209 10.1016/j.neuron.2013.08.035 10.1016/j.nbd.2007.07.016 Tavares Gomes A.L., 2009, Purinergic modulation in the development of the rat uncrossed retinotectal pathway, Neuroscience, 163, 1061, 10.1016/j.neuroscience.2009.07.029 10.1016/j.brainres.2006.03.107 Trindade P., 2011, Evidence for a role of calcineurin in the development of retinocollicular fine topography, Neurosci. Lett., 487, 47, 10.1016/j.neulet.2010.09.071 10.1016/S0301-0082(03)00089-3 Vella L.J., 2012, Identification of a novel amyloid precursor protein processing pathway that generates secreted N‐terminal fragments, FASEB J., 26, 2930, 10.1096/fj.11-200295 Vierci G., 2013, Creb is modulated in the mouse superior colliculus in developmental and experimentally‐induced models of plasticity, Int. J. Dev. Neurosci., 31, 46, 10.1016/j.ijdevneu.2012.10.003 10.1523/JNEUROSCI.4660-04.2005 10.1523/JNEUROSCI.2132-09.2009 10.1016/j.nbd.2011.12.047 10.1038/nature14864 10.1523/JNEUROSCI.5369-11.2012 10.1111/j.1440-169X.2011.01282.x 10.1038/nm0103-3 10.1523/JNEUROSCI.4701-07.2007 10.1146/annurev-neuro-062111-150455