Fig. 2

The main redox signaling-associated mechanisms and their cross-talk in AD progression. NOX, TGF-β, NF-κB and Nrf2 are remarkable mediators of oxidative stress that implicated in AD development. NOX is dedicated contributor Aβ-induced ROS generation, and NOX signaling pathway is closely associated with Aβ deposition and cognitive deficits. TGF-β/Smad signaling also promotes ROS production, and NOX4 is the main cause of TGF-β induced ROS generation via TGF-β/Smad/ROS signaling cascade. In addition, tau protein hyperphosphorylation is another hallmark of AD, which could deteriorate AD through TGF-β/Smad/NOX4/ERK1/2/tau protein cascade. Moreover, metal ions and NF–κB also contributes to AD progression by accelerating ROS and inflammation respectively, while Nrf2 shows potential protective effect against AD via promoting anti-oxidant responses and inhibiting NF–κB. Maxacalcitol is a vitamin D analogue that significantly alleviates cognitive impairment of AD rats through elevating Nrf2, restraining inflammation and reducing the hyperphosphorylation of tau proteins. ERK: extracellular signal-related kinase; GCLM: glutamate-cysteine ligase modifier subunit; HO-1: haem oxygenase-1; Keap1: Kelch-like ECH-associted protein 1; MEK: mitogen-activated protein kinase/extracellular signal-related kinase; NQO1: NAD(P)H dehydrogenase quinone 1, SARA: smad anchor for receptor activation