Oasi Maria Institute for Research and Care on Mental Retardation and Brain Aging, Neuropharmacology Section, 94018 Troina, Italy.
J Neurosci. 2013 Jan 23;33(4):1462-85. doi: 10.1523/JNEUROSCI.3206-12.2013.
Aging and exposure to environmental toxins including MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) are strong risk factors for developing Parkinson's disease (PD), a common neurologic disorder characterized by selective degeneration of midbrain dopaminergic (DAergic) neurons and astrogliosis. Aging and PD impair the subventricular zone (SVZ), one of the most important brain regions for adult neurogenesis. Because inflammation and oxidative stress are the hallmarks of aging and PD, we investigated the nature, timing, and signaling mechanisms contributing to aging-induced SVZ stem/neuroprogenitor cell (NPC) inhibition in aging male mice and attempted to determine to what extent manipulation of these pathways produces a functional response in the outcome of MPTP-induced DAergic toxicity. We herein reveal an imbalance of Nrf2-driven antioxidant/anti-inflammatory genes, such as Heme oxygenase1 in the SVZ niche, starting by middle age, amplified upon neurotoxin treatment and associated with an exacerbated proinflammatory SVZ microenvironment converging to dysregulate the Wingless-type MMTV integration site (Wnt)/β-catenin signaling, a key regulatory pathway for adult NPCs. In vitro experiments using coculture paradigms uncovered aged microglial proinflammatory mediators as critical inhibitors of NPC proliferative potential. We also found that interruption of PI3K (phosphatidylinositol3-kinase)/Akt and the Wnt/Fzd/β-catenin signaling cascades, which switch glycogen synthase kinase 3β (GSK-3β) activation on and off, were causally related to the impairment of SVZ-NPCs. Moreover, a synergy between dysfunctional microglia of aging mice and MPTP exposure further inhibited astrocyte proneurogenic properties, including the expression of key Wnts components. Last, pharmacological activation/antagonism studies in vivo and in vitro suggest the potential that aged SVZ manipulation is associated with DAergic functional recovery.
衰老和暴露于环境毒素，包括 MPTP（1-甲基-4-苯基-1,2,3,6-四氢吡啶），是导致帕金森病（PD）的强烈危险因素，PD 是一种常见的神经紊乱疾病，其特征是中脑多巴胺能（DAergic）神经元的选择性退化和星形胶质细胞增生。衰老和 PD 会损害侧脑室下区（SVZ），SVZ 是成年神经发生最重要的脑区之一。由于炎症和氧化应激是衰老和 PD 的标志，我们研究了导致衰老雄性小鼠 SVZ 干细胞/神经祖细胞（NPC）抑制的性质、时间和信号机制，并试图确定在多大程度上操纵这些途径会对 MPTP 诱导的 DAergic 毒性产生功能反应。我们在此揭示了 SVZ 生态位中 Nrf2 驱动的抗氧化/抗炎基因（如血红素加氧酶 1）的失衡，从中年开始，在神经毒素治疗时加剧，并与加剧的 SVZ 促炎微环境相关，导致 Wnt 型 MMV 整合位点（Wnt）/β-连环蛋白信号通路失调，这是成年 NPC 的关键调节途径。使用共培养范式的体外实验揭示了衰老的小胶质细胞促炎介质作为 NPC 增殖潜力的关键抑制剂。我们还发现，PI3K（磷脂酰肌醇 3-激酶）/Akt 和 Wnt/Fzd/β-连环蛋白信号级联的中断，这些信号级联开关糖原合酶激酶 3β（GSK-3β）的激活和失活，与 SVZ-NPC 的损伤有关。此外，衰老小鼠的功能失调小胶质细胞与 MPTP 暴露之间的协同作用进一步抑制了星形胶质细胞的神经发生特性，包括关键 Wnt 成分的表达。最后，体内和体外的药理学激活/拮抗研究表明，SVZ 老化的操纵与 DAergic 功能恢复有关。
