Dementia is a prevalent public disease, has approximately 47 million patients in worldwide, and this number is expected to increase to 131 million by 2050(Arvanitakis et al., 2019). It is most commonly attributed to Alzheimer's disease (AD), accounting for an estimated 60–70% of cases of worldwide(Scheltens et al., 2021). Especially, individuals who suffer from dementia are more vulnerable to COVID-19 and related morbidity(Baranova et al., 2022) and this caused the heaviest social burden to the aging society.

Amyloid-β (Aβ) plaques in the brain is recognized as the pathological hallmarks of AD. However, mountains of evidence indicate that the Aβ cascade alone cannot fully elucidate much of the pathogenesis of AD. Elevated levels of inflammatory cytokines were observed in AD patients’ brain(Leng and Edison, 2021), which indicates neuroinflammation plays a vital role in AD as well. Microglia, a housekeeper in the neuroimmune system, has unique sentinel and defense functions to protect neurons according to phenotypic polarization(Hickman et al., 2018). M1 represents a pro-inflammatory phenotype and secretes inflammatory cytokines, and M2 represents an anti-inflammatory phenotype and produces anti-inflammatory cytokines(Wu et al., 2021). The phenotypic shift from M2-dominant to M1-dominant could lead to inflammatory pathological injury in AD(Xue et al., 2021). Targeting M2 phenotype polarization been found to be a potential therapeutic strategy(Hu et al., 2015), and recent advances in our understanding of microglia have identified it is closely related to triggering receptor expressed on myeloid cells 2 (TREM2)(Ulland and Colonna, 2018). TREM2 is highly specific and expressed by microglia and is a direct regulator known to sustain microglial activation in AD pathology(Cignarella et al., 2020), intersecting cellular responses to Aβ in neurons(Nguyen et al., 2020b). Mountains of evidence suggest that TREM2-dependent microglial activation plays a vital role in delaying AD onset or progression(Nguyen et al., 2020a).

Alpinae Oxyphyllae Fructus (AE) is the dried ripe fruits of Alpinia oxyphylla Miq.(Zingiberaceae) and is widely used as a traditional Chinese medicine with diverse effects on warming kidney and spleen, improving cognitive ability, anti-oxidative stress, and protecting neurons(Huang et al., 2019; Wang et al., 2018a). Our previous studies found that AE can reverse the cognitive impairments in Aβ-induced mice(Shi et al., 2014, 2015) and show a promising inhibitory effect on neuroinflammation in LPS-induced mice as well(Wang et al., 2018a; Yan et al., 2021). In addition, the increased Iba-1 levels induced by LPS were restored after AE treatment(Wang et al., 2018b), indicating AE protects against neuroinflammation might by regulating microglia activation. However, the detailed mechanism between AE and microglia is unclear. In the present study, we intend to further investigate the regulatory effects of AE on microglia in LPS-induced BV2 cells, explore the potential mechanisms involved in the transition of microglial phenotypes and anti-neuroinflammation effects in AD, and identify the potential active compounds in AE.