Quercetin Regulates the Polarization of Microglia through the NRF2/HO1 Pathway and Mitigates Alzheimer's Disease

Alzheimer's disease (AD) is a burdening disease and is the main cause of dementia. Quercetin (Que), an antioxidant, plays potential roles in treating age-related disorders, including AD. This study aimed to validate the effects of Que on AD and explore the underlying mechanisms. Mice with no treatment, amyloid-β Aβ (1-42) treatment (for acquiring AD model), or Aβ (1-42) plus Que treatment were used. Cognitive function was determined using the open field test (OFT), objective recognition test, and Y-maze test. In brain tissues, mRNA levels of inflammation cytokines, the M1 microglia marker cluster of differentiation (CD)86, and the M2 microglia markers arginase 1 (Arg1) and CD206 were measured. Nuclear factor E2-related factor 2 (NRF2)/heme oxygenase-1 (HO1) pathway-related proteins were detected by western blot. Additionally, mechanisms were investigated using human microglia HMC3 cells treated with Aβ (1-42) and Aβ (1-42) plus Que. The NRF2/HO1 pathway in HMC3 cells was inhibited using the selective inhibitor ML385. Cell viability and death were assessed using the cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) release levels, respectively. Cell apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Levels of NRF2/HO1 pathway-related proteins, inflammation cytokines, and oxidative stress-related markers, including malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (reduced glutathione (GSH)/oxidized glutathione disulfide (GSSG)), were determined in HMC3 cells. Flow cytometry was used to determine M1 markers CD86 and CD80 and M2 markers CD206 and CD163. Cognitive ability was impaired in AD model mice, and Que treatment reversed this impairment (p < 0.05). Levels of interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), and IL-6 were increased, while M2 markers were decreased in the AD model mouse brain. Que treatment reversed these changes (p < 0.001). The NRF2/HO1 pathway was slightly inhibited in AD mice brain, while further activated by Que (p < 0.05). Que reversed the Aβ (1-42)-impaired cell viability. Through greatly activating NRF2/HO1 pathway, Que suppressed Aβ (1-42)-induced cell death, decreased Aβ (1-42)-promoted IL-1β, TNF-α, IL-6, MDA, CD86 and CD80, increased Aβ (1-42)-suppressed SOD and GSH/GSSG, and greatly increased CD206 and CD163 (p < 0.01). Quercetin, through the activation of the NRF2/HO1 pathway, promotes M2 polarization of microglia, suppresses Aβ (1-42)-