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

Background: 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. Methods: Mice with no treatment, amyloid-beta A beta (1-42) treatment (for acquiring AD model), or A beta (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 A beta (1-42) and A beta (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. Results: Cognitive ability was impaired in AD model mice, and Que treatment reversed this impairment (p < 0.05). Levels of interleukin (IL)-1 beta, tumor necrosis factor-alpha (TNF-alpha), 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 A beta (1-42)-impaired cell viability. Through greatly activating NRF2/HO1 pathway, Que suppressed A beta (1-42)-induced cell death, decreased A beta (1-42)-promoted IL-1 beta, TNF-alpha, IL-6, MDA, CD86 and CD80, increased A beta (1-42)-suppressed SOD and GSH/GSSG, and greatly increased CD206 and CD163 (p < 0.01). Conclusion: Quercetin, through the activation of the NRF2/HO1 pathway, promotes M2 polarization of microglia, suppresses A beta (1-42)-induced inflammation and oxidative stress, protects microglia from A beta (1-42)-induced damage, improves cognitive function in mice, and demonstrates therapeutic potential for AD.