Microglial polarization plays an essential role in the progression and regression of neurodegenerative disorders. Cyanidin-3-O-glucoside (C3G), a dietary anthocyanin found in many fruits and vegetables, has been reported as an antioxidant, anti-inflammatory, and antitumor agent. However, there have been no reports on whether C3G can regulate the M1/M2 shift in an Alzheimer’s disease model. We attempted to investigate the effects of C3G on M1/M2 polarization and the mechanism to regulate anti-inflammation and phagocytosis, both in vitro and in vivo. HMC3 cells were treated with β-amyloid (Aβ42) in the presence or absence of 50 μM C3G for different time intervals, and APPswe/PS1ΔE9 mice were orally administered 30 mg/kg/day of C3G for 38 weeks. The in vitro data revealed that C3G could shift the M1 phenotype of microglia to M2 by reducing the expression of M1-specific markers (CD86 and CD80), inflammatory cytokines (IL-Iβ, IL-6, TNF-α), reactive oxygen species, and enhancing the expression of M2-specific markers (CD206 and CD163). The APPswe/PS1ΔE9 mice results were consistent with the in vitro data, indicating a significant reduction in inflammatory cytokines and higher expression of M2-specific markers such as CD206 and Arg1 in C3G-treated Alzheimer’s disease model mice. Additionally, C3G was found to upregulate PPARγ expression levels both in vitro and in vivo, whereas a PPARγ antagonist (GW9662) was found to block C3G-mediated effects in vitro. In this study, we confirmed that C3G could regulate microglial polarization by activating PPARγ and eliminating accumulated β-amyloid by enhancing Aβ42 phagocytosis through the upregulation of TREM2.
Microglial polarization to the M1 phenotype (classically activated) or the M2 phenotype (alternatively activated) is critical in determining the fate of immune responses in neurodegenerative diseases (NDs). M1 macrophages contribute to neurotoxicity, neuronal and synaptic damage, and oxidative stress and are the first line of defense, and M2 macrophages elicit an anti-inflammatory response to regulate neuroinflammation, clear cell debris, and promote neuroregeneration. Various studies have focused on the ability of natural compounds to promote microglial polarization from the M1 phenotype to the M2 phenotype in several diseases, including NDs. However, studies on the roles of fatty acids in microglial polarization and their implications in NDs are a rare find. Most of the studies support the role of polyunsaturated fatty acids (PUFAs) in microglial polarization using cell and animal models. Thus, we aimed to collect data and provide a narrative account of microglial types, markers, and studies pertaining to fatty acids, particularly PUFAs, on microglial polarization and their neuroprotective effects. The involvement of only PUFAs in the chosen topic necessitates more in-depth research into the role of unexplored fatty acids in microglial polarization and their mechanistic implications. The review also highlights limitations and future challenges.
Objective: Alzheimer’s disease (AD) is a neurodegenerative disease that abolishes cognitive and analytical abilities to perform basic day-to-day tasks. Microglia are involved in AD-associated neuroinflammation in response to amyloid β‐peptide (Aβ). This study focused on observing the immunomodulatory effects of 9-cis-retinoic acid (9-Cis-RA) the active metabolite of vitamin A, on Aβ-treated human microglial HMO6 cells. Methods: HMO6 cells were treated with Aβ42 in the absence or presence of 9-cis-RA, and the expression of M1-and M2-associated molecules, Toll like receptors (TLRs), and triggering receptor expressed on myeloid cells 2 (TREM2) were examined. Results: The levels of M1-markers [cluster of differentiation (CD86) and inducible nitric oxide synthase (iNOS)] and -cytokines [tumor necrosis factor (TNF-α), interleukin (IL)-6, and IL-1β], inflammatory receptors (TLR2 and TLR4), and reactive oxygen species increased significantly in Aβ-treated HMO6 cells. In contrast, the levels of M2-markers (CD206 and arginase-1) and -cytokines (IL-10, IL-4, and C-C motif chemokine ligand 17) the anti-inflammatory receptor TLR10 was significantly suppressed. However, 9-cis-RA treatment reversed the Aβ-induced upregulation of expression of M1-associated molecules and upregulated the expression of M2-associated molecules. Moreover, 9-cis-RA treatment augmented Aβ uptake by HMO6 cells, possibly by increasing the cell surface protein levels of TREM2, which is a receptor of Aβ that promotes Aβ phagocytosis by microglia. Conclusion: Our results suggest that 9-cis-RA is a potential therapeutic agent for AD.
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