Aging-induced Nrf2-ARE pathway disruption in the subventricular zone drives neurogenic impairment in parkinsonian mice via PI3/Akt/Wnt/β-catenin signaling dysregulation

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 most predominant brain region for adult neurogenesis. Because inflammation and oxidative stress are the hallmarks of ageing and PD, we investigated the nature, timing and signaling mechanisms contributing to ageing-induced SVZ stem/neuroprogenitor cell (NPC) inhibition in ageing male mice and addressed to what extent does manipulation of these pathways have a functional response in the outcome of MPTP-induced DAergic toxicity. We herein unveil a disbalance of Nrf2-driven anti-oxidant/anti-inflammatory genes, such as Heme oxygenase1 (Homox) in SVZ niche, starting by middle-age, amplified upon neurotoxin treatment and interconnected with dysregulation of Wingless-type MMTV integration site (Wnt)/β-catenin signaling, a key regulatory pathway for adult neurogenesis. Ex vivo and in vitro studies in primary NPCs supported neurogenic impairment, a condition mimicked by exposure of young NPCs to aged microglia. Pharmacological mitigation of exacerbated SVZ microenvironment in ageing mice, in vitro and in vivo rescued SVZ neurogenic potential via normalization of Nrf2-Homox axis leading to PI3K/Akt-mediated-Wnt/β-catenin activation and protected nigrostriatal DAergic neurons against MPTP toxicity, with therapeutical implications for age-dependent neurodegenerative disorders, including PD.