Aging-Induced Nrf2-ARE Pathway Disruption in the Subventricular Zone Drives Neurogenic Impairment in Parkinsonian Mice via PI3K-Wnt/β-Catenin 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 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)/beta-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/beta-catenin signaling cascades, which switch glycogen synthase kinase 3 beta (GSK-3 beta) 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.