Microglia Polarization, Gene-Environment Interactions and Wnt/β-Catenin Signaling: Emerging Roles of Glia-Neuron and Glia-Stem/Neuroprogenitor Crosstalk for Dopaminergic Neurorestoration in Aged Parkinsonian Brain

Abstract

Neuroinflammatory processes are recognized key contributory factors in Parkinson's disease (PD) physiopathology. While the causes responsible for the progressive loss of midbrain dopaminergic (mDA) neuronal cell bodies in the subtantia nigra pars compacta are poorly understood, aging, genetics, environmental toxicity, and particularly inflammation, represent prominent etiological factors in PD development. Especially, reactive astrocytes, microglial cells, and infiltrating monocyte-derived macrophages play dual beneficial/harmful effects, via a panel of pro- or anti-inflammatory cytokines, chemokines, neurotrophic and neurogenic transcription factors. Notably, with age, microglia may adopt a potent neurotoxic, pro-inflammatory “primed” (M1) phenotype when challenged with inflammatory or neurotoxic stimuli that hamper brain's own restorative potential and inhibit endogenous neurorepair mechanisms. In the last decade we have provided evidence for a major role of microglial crosstalk with astrocytes, mDA neurons and neural stem progenitor cells (NSCs) in the MPTP- (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-) mouse model of PD, and identified Wnt/β-catenin signaling, a pivotal morphogen for mDA neurodevelopment, neuroprotection, and neuroinflammatory modulation, as a critical actor in glia-neuron and glia-NSCs crosstalk. With age however, Wnt signaling and glia-NSC-neuron crosstalk become dysfunctional with harmful consequences for mDA neuron plasticity and repair. These findings are of importance given the deregulation of Wnt signaling in PD and the emerging link between most PD related genes, Wnt signaling and inflammation. Especially, in light of the expanding field of microRNAs and inflammatory PD-related genes as modulators of microglial-proinflammatory status, uncovering the complex molecular circuitry linking PD and neuroinflammation will permit the identification of new druggable targets for the cure of the disease. Here we summarize recent findings unveiling major microglial inflammatory and oxidative stress pathways converging in the regulation of Wnt/β-catenin signaling, and reciprocally, the ability of Wnt signaling pathways to modulate microglial activation in PD. Unraveling the key factors and conditons promoting the switch of the proinflammatory M1 microglia status into a neuroprotective and regenerative M2 phenotype will have important consequences for neuroimmune interactions and neuronal outcome under inflammatory and/or neurodegenerative conditions.

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

“…Other studies, however, showed no difference in proliferation or differentiation of newborn cells in the SGZ of the DG after DAergic lesions (Ermine et al, and refs therein). As different factors including age, sex, inflammation, the brain region examined, and the post‐injury interval considered, significantly affect the NSC response to injury (Figure ; and Figure S1) (Khan, Wakade, de Sevilla, Brann, ; L'Episcopo, , ; L'Episcopo, Tirolo, Serapide, et al, ; Tatar, Bessert, Tse, Skoff, , and following sections), it seems plausible that impairment of SVZ and SGZ neurogenesis in PD may well depend on both DAergic and non‐DAergic related mechanisms.…”

“…Astrocyte dysfunctions with age and neurodegeneration are well recognized processes leading to a marked downregulation of astrocyte's supportive, neuroprotective and pro‐neurogenic properties (Barkho et al, ; Jiao & Chen, ; L'Episcopo, Tirolo, Peruzzotti‐Jametti, et al, ; L'Episcopo, Tirolo, Serapide, et al, ; Marchetti & Abbracchio, ; Marchetti et al, ; Sousa‐Victor et al, ; Yang et al, ). Within the SVZ niche, astrocyte dysfunction as a consequence of age and exposure to the PD neurotoxin was shown to inhibit both proliferation and neuroblast formation, as observed both in vivo and in vitro.…”

“…The question therefore arises as to whether it is possible to counteract these age‐dependent and region‐specific restrictive mechanisms inhibiting DAergic plasticity, in order to re‐activate the endogenous neurorepair and regeneration programs in the aged PD brain. In the last decade, we have explored the functional role of adult neurogenesis in PD by addressing the molecular and cellular NSC regulatory mechanisms underlying the age‐dependent decline of neurogenic potential in a 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine/1‐methyl‐4‐phenylpyridinium (MPTP/MPP + )‐induced rodent model of basal ganglia injury, investigating the potential to stimulate adult neurogenesis as a means to support neuroprotective and neurorestorative therapies (L'Episcopo, Serapide, et al, ; L'Episcopo et al, , , , ; L'Episcopo, Tirolo, Serapide, et al, ; Marchetti, ; Marchetti et al, ; Marchetti & Pluchino, ). Particularly, we concentrated on the key pathway regulating DAergic neurogenesis, from neurodevelopment through aging and neurodegeneration: the wingless‐type mouse mammary tumor virus integration site (Wnt)/β‐catenin (WβC) signalling cascade (Brodski, Blaess, Partanen, & Prakash, ; Inestrosa & Arenas, ; Maiese, ; Maiese, Faqi, Chong, & Shang, ; Marchetti, ; Nusse & Clevers, ; Nusse & Varmus, ; Palomer et al, ; Salinas, ; Tapia‐Rojas & Inestrosa, ; Toledo et al, ; Wurst & Prakash, ).…”

“…The critical role of astrocyte‐derived Wnt1 and WβC‐signalling was further shown in the Aq‐PVR DAergic niche, where WβC controls the fate specification of adult DAergic precursors (L'Episcopo et al, , ). Conversely, aging‐dependent oxidative stress and inflammatory pathways correlate with a downregulation of WβC ‐ signalling in NSC niches and a dramatic up‐regulation of endogenous Wnt‐antagonists, with implications for SVZ neurogenesis, Aq‐PVR‐NSC activation, and DAergic self‐repair ability (L'Episcopo et al, , , ; L'Episcopo, Tirolo, Serapide, et al, ; Marchetti et al, ). In 2013, these findings inspired the perspective, “ Wnt your brain be inflamed?…”

“…The mechanisms underlying these phenomena constitute a synergy between (a) the upregulation of proinflammatory glial pathways, (b) the decline of anti‐oxidant self‐defence mechanisms, such as the nuclear factor erythroid‐2‐related factor 2 (Nrf2) ‐heme oxygenase 1 (Hmox1) axis, a key mediator of cellular adaptive response, and (c) the decline of astrocyte‐derived Wnts leading to NSC neurogenic impairment, with a consequent failure to recover from a PD insult. As a result, both pharmacological and cellular therapies involving the up‐regulation of WβC‐signalling and immunomodulation were reported to ameliorate the aged microenvironment, thereby promoting endogenous neurogenesis, ultimately boosting a full neurorestoration program in the aged PD brain (L'Episcopo et al, , , ; L'Episcopo et al, ; L'Episcopo, Tirolo, Serapide, et al, ; Marchetti, ; Marchetti et al, ; Marchetti & Pluchino, ). While little is known on WβC ‐ signalling in the PD‐injured hippocampus, it seems plausible that a comparable dysfunction of the WβC ‐ pathway may well be at play in the SGZ of the DG, with potential consequences for hippocampal neurogenesis in PD and its involvement in non‐motor symptoms of PD.…”