Boosting Antioxidant Self-defenses by Grafting Astrocytes Rejuvenates the Aged Microenvironment and Mitigates Nigrostriatal Toxicity in Parkinsonian Brain via an Nrf2-Driven Wnt/β-Catenin Prosurvival Axis.

Maria Francesca Serapide,Francesca L’Episcopo,Carmela Giachino,Bianca Marchetti,Salvatore Caniglia,Cataldo Tirolo,Nunzio Testa

doi:10.3389/fnagi.2020.00024

Abstract

Astrocyte (As) bidirectional dialog with neurons plays a fundamental role in major homeostatic brain functions, particularly providing metabolic support and antioxidant self-defense against reactive oxygen (ROS) and nitrogen species (RNS) via the activation of NF-E2-related factor 2 (Nrf2), a master regulator of oxidative stress. Disruption of As–neuron crosstalk is chiefly involved in neuronal degeneration observed in Parkinson’s disease (PD), the most common movement disorder characterized by the selective degeneration of dopaminergic (DAergic) cell bodies of the substantia nigra (SN) pars compacta (SNpc). Ventral midbrain (VM)-As are recognized to exert an important role in DAergic neuroprotection via the expression of a variety of factors, including wingless-related MMTV integration site 1 (Wnt1), a principal player in DAergic neurogenesis. However, whether As, by themselves, might fulfill the role of chief players in DAergic neurorestoration of aged PD mice is presently unresolved. Here, we used primary postnatal mouse VM-As as a graft source for unilateral transplantation above the SN of aged 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice after the onset of motor symptoms. Spatio-temporal analyses documented that the engrafted cells promoted: (i) a time-dependent nigrostriatal rescue along with increased high-affinity synaptosomal DA uptake and counteraction of motor deficit, as compared to mock-grafted counterparts; and (ii) a restoration of the impaired microenvironment via upregulation of As antioxidant self-defense through the activation of Nrf2/Wnt/β-catenin signaling, suggesting that grafting As has the potential to switch the SN neurorescue-unfriendly environment to a beneficial antioxidant/anti-inflammatory prosurvival milieu. These findings highlight As-derived factors/mechanisms as the crucial key for successful therapeutic outcomes in PD.

Highlights

Astrocyte (As) bidirectional dialog with neurons plays a fundamental role in major homeostatic brain functions
As a first step of our transplantation protocol, primary Ventral midbrain (VM)-As cultures established from postnatal days 2–3 (P2–3) and cultured as described for 14–20 DIV were processed for qPCR and immunocytochemical analyses to identify astrocytic (GFAP, S100B, ALDHL1) markers and verify the purity of the preparation by testing several non-astrocytic identity markers (Figures 1A,B)
P2–3 VM-As were shown to promote the differentiation of adult midbrain- but not subventricular zone (SVZ) neural stem progenitor cells (NSCs) into functionally active DAergic neurons, in vitro (L’Episcopo et al, 2011b, 2014a)

Summary

Introduction

Astrocyte (As) bidirectional dialog with neurons plays a fundamental role in major homeostatic brain functions. Besides their physical and metabolic support to neurons, As regulate central nervous system (CNS) synaptogenesis, promote neuronal development and plasticity, guide axon pathfinding, modulate the blood–brain barrier, and contribute to neuroprotection via the production of different growth and neurotrophic factors, antioxidant and anti-inflammatory molecules, through a concerted crosstalk with neurons (Marchetti and Abbracchio, 2005; Bélanger and Magistretti, 2009; Sofroniew and Vinters, 2010; Molofsky et al, 2012; Sun and Jakobs, 2012). While the causes and mechanisms are not completely understood, current evidence indicates that a complex interplay between several genes and many environmental factors affecting the regulation of crucial pathways involved in inflammatory glial activation, mitochondrial function, protein misfolding/aggregation, and autophagy contribute to DAergic neuron demise in PD (Marchetti and Abbracchio, 2005; Frank-Cannon et al, 2008; Gao et al, 2011; Lastres-Becker et al, 2012; Cannon and Greenamyre, 2013; Hirsch et al, 2013; Dzamko et al, 2015, 2017; Langston, 2017; Blauwendraat et al, 2019)

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