| Popis: |
Background: Increasing evidence indicates that Alzheimer’s disease (AD) is not only a disease of the brain but also an autoimmune disorder of innate immunity. Pyroptosis-mediated inflammation activates microglia, which are innate immune regulators that play an important role in AD formation. New studies have found that some peripheral proinflammatory cytokines can penetrate the blood–brain barrier (BBB), thereby activating microglial pyroptosis and promoting inflammation in the brain. However, the impact of the liver-brain axis on the development of AD remains elusive. Here, we show that liver-secreted ANGPTL8 acts as an inflammatory trigger and penetrates the BBB, contributing to the progression of AD. Methods: ANGPTL8-/- mice were crossed with 5×FAD mice to obtain WT, 5×FAD, ANGPTL8-/-, and ANGPTL8-/- 5×FAD mice. We checked whether ANGPTL8 knockout affected learning and memory impairment using the Morris water maze (MWM) task. Tiofavin-S (Tio-S) and Nissl staining were used to analyze amyloid β (Aβ) deposition and the number of neurons in the four groups of mice. The effects of ANGPTL8 on the activation of microglia and neuroinflammation were analyzed in vitro and in vivo by immunofluorescence and flow cytometry. Extracting single-cell sequencing library data and in situ hybridization, etc., were used to analyze the source of ANGPTL8 that promotes AD progression. RNA interference assay, transmission electron microscopy, western blotting, etc., were used to study the mechanisms of ANGPTL8 in regulating AD progression. Finally, drug screening was used to identify an effective inhibitor of ANGPTL8. Results: ANGPTL8 knockout improved cognitive functions and decreased Ab deposition in 5xFAD mice. ANGPTL8 levels were significantly increased in the livers of 5xFAD mice and upregulated by Aβ stimulation. Secreted Aβ in turn promotes the expression of ANGPTL8, and secreted ANGPTL8 acts as an inflammatory trigger and directly interacts with the microglia membrane receptor PIRB to activate downstream PIRB/NLRP3 signaling, thereby inhibiting the phagocytic capacity of microglia to reduce the clearance of Aβ by promoting pyroptosis. The antidiabetic drug metformin can inhibit the expression of ANGPTL8 and improve the learning and memory of 5xFAD mice. Conclusions: Our study identified ANGPTL8 as a novel peripheral inflammatory trigger that regulates the liver-brain axis and aggravates microglial pyroptosis via the PIRB/NLRP3 pathway to accelerate the pathogenesis of AD. Our results also indicate that the serum ANGPTL8 level represents a potential diagnostic marker for diseases featuring AD and that targeting ANGPTL8 holds great promise for developing innovative therapies to treat AD. |
