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Restauration of age related motor impairment: Role of IGF-1 based gene therapy and microglial activation.

Eugenia Falomir Lockhart1, Claudia B. Herenu1 and Maria J. Bellini1*
  • 1 Argentinian National Council of Scientific Research (CONICET), Institute for Biochemical Research (INIBIOLP), School of Medicine, National University of La Plata, Argentina, Argentina

Microglial cells play an important role in healthy and diseased brain removing apoptotic neurons (Perry et al., 1985; Ashwell, 1990; Calderó et al., 2009; Sierra et al., 2010), establishing transient connections with neuronal synapses (Wake et al., 2009) and producing neurotrophic factors that modulate neurogenesis during embryogenesis and adulthood (Ueno et al., 2013; Xia et al., 2015).These cells are essential for ensuring neuroprotection in the normal and pathological condition of central nervous system as they are an important sources of neurotrophic factors. It has been described that aging reduces the ability of microglia to provide neuroprotection (Streit and Xue, 2014; Floden and Combs, 2011; Harry, 2013, Orre et al., 2014, Suh et al., 2013). Microglia-mediated neuroprotection has been described in the nervous system (Polazzi and Contestabile, 2002; Lai and Todd, 2008). Several studies have shown that, after axotomy of the motor axons of the facial nerve, the injured neurons regenerate when activated microglial cells are present (reviewed in Raivich, 2002), being the activation of microglia crucial for the regeneration to happen. Moreover, transplantation studies showing that engraftment of cultured microglial cells into the injured spinal cord promotes neurite growth into such microglial grafts (Rabchevsky and Streit, 1997) support this idea that microglial neuroinflammation is a vital component of the regenerative process. Previous studies of our group described that intracerebroventricular (ICV) Insulin-like growth factor-I (IGF-I) gene therapy induced a significant improvement in motor performance in aged rats (Sanchez et al., 2008, Nishida et al., 2011). Several works report that IGF-I stimulates microglia proliferation (O’Donnell et al., 2002;). We propose that restorative effects of IGF-I in motor skills could be mediated by glial cells. In the current study we implemented ICV IGF-I gene therapy in very old rats (28 months) and assessed the motor performance pre and 17-days after surgery. Glial immunoreactivity in striatum was evaluated by Iba1 and GFAP markers. Results: As we previously reported, IGF-I restored motor coordination and forelimb grip strength in aged rats (Sanchez et al., 2008). We found that microglia immunoreactivity (Iba-1+) was significantly increased for at least 17 days after treatment with IGF-I (Xm-senil-IGF-I=8.370±0.3297 vs Xm-senil-DsRed= 5.557±0.2553; p<0.0001), astrocytes (GFAP+) showed not changes. Our results identify a novel function of microglia in the maintenance of motor permormance and suggest an original approach for reversing age-associated motor and exploratory performance recorded in rats.

References

Ashwell K. (1990). Microglia and cell death in the developing mouse cerebellum. Brain Res. Dev. Brain Res. 55:219–230.
Calderó J, Brunet N, Ciutat D, Hereu M, Esquerda JE. (2009). Development of microglia in the chick embryo spinal cord: implications in the regulation of motoneuronal survival and death. J. Neurosci. Res. 87:2447–2466.
Floden AM and Combs CK. (2011). Microglia demonstrate age-dependent interaction with amyloid-β fibrils. J. Alzheimers Dis. 25:279–293
Harry GJ. (2013). Microglia during development and aging. Pharmacol. Ther. 139:313–326.
Lai AY, Todd KG. (2008) Differential regulation of trophic and proinflammatory microglial effectors is dependent on severity of neuronal injury. Glia. 56:259–270.
Nishida F, Morel GR, Hereñú CB, Schwerdt JI, Goya RG, Portiansky EL. (2011). Restorative effect of intracerebroventricular insulin-like growth factor-I gene therapy on motor performance in aging rats. Neuroscience.177:195-206.
O’Donnell SL, Frederick TJ, Krady JK, Vannucci SJ, Wood TL. (2002). IGF-I and microglia/macrophage proliferation in the ischemic mouse brain Glia. 39:85–97.
Orre M, Kamphuis W, Osborn LM, Jansen AH, Kooijman L, Bossers K, et al. (2014). Isolation of glia from Alzheimer’s mice reveals inflammation and dysfunction. Neurobiol. Aging 35:2746–2760.
Perry VH, Hume DA and Gordon S. (1985). Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience 15, 313–326.
Polazzi E and Contestabile A. (2002). Reciprocal interactions between microglia and neurons: from survival to neuropathology. Rev Neurosci. 13:221–242.
Rabchevsky and Streit. (1997). Grafting of cultured microglial cells into the lesioned spinal cord of adult rats enhances neurite outgrowth. J Neurosci Res. 47(1):34-48.
Raivich G. (2002). Microglial response in the axotomized facial motor nucleus. In: Streit WJ, editor. Microglia in the regenerating and degenerating central nervous system. New York: Springer-Verlag. p166–187.
Sanchez HL, Silva LB, Portiansky EL, Herenu CB, Goya RG, Zuccolilli GO. (2008) Dopaminergic mesencephalic systems and behavioral performance in very old rats. Neuroscience 154(4):1598-606.
Sierra A, Encinas JM, Deudero JJP, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, Tsirka SE and Maletic-Savatic M. (2010). Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7:483–495.
Streit WJ and Xue QS. (2014) Human CNS immune senescence and neurodegeneration. Curr Opin Immunol. 29C:93-96.
Suh HS, Zhao ML, Derico L, Choi N, Lee SC. (2013). Insulin-like growth factor 1 and 2 (IGF1, IGF2) expression in human microglia: differential regulation by inflammatory mediators. J Neuroinflammation. 12;10:37
Ueno M, Fujita Y, Tanaka T, Nakamura Y, Kikuta J, Ishii M and Yamashita T. (2013). Layer V cortical neurons require microglial support for survival during postnatal development. Nat. Neurosci. 16:543–551.
Wake H, Moorhouse AJ, Jinno S, Kohsaka S and Nabekura J. (2009). Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29:3974–3980.
Xia CY, Zhang S, Gao Y, Wang ZZ, Chen NH. (2015) Selective modulation of microglia polarization to M2 phenotype for stroke treatment. Int Immunopharmacol. 25(2):377-382

Keywords: IGF-I, Aging, motor impairment, Microglia, Gene Therapy

Conference: Latin-American School on glial cells in the diseased brain (IBRO), Bogotá, Colombia, 13 Jul - 17 Jul, 2015.

Presentation Type: Poster Presentation

Topic: Neurodegenerative diseases

Citation: Falomir Lockhart E, Herenu CB and Bellini MJ (2015). Restauration of age related motor impairment: Role of IGF-1 based gene therapy and microglial activation.. Conference Abstract: Latin-American School on glial cells in the diseased brain (IBRO). doi: 10.3389/conf.fncel.2015.35.00010

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Received: 15 May 2015; Published Online: 11 Jun 2015.

* Correspondence: Dr. Maria J Bellini, Argentinian National Council of Scientific Research (CONICET), Institute for Biochemical Research (INIBIOLP), School of Medicine, National University of La Plata, Argentina, La Plata, Buenos Aires, 1900, Argentina, mariajosebellini@yahoo.com