RvD1 signaling in peripheral macrophages promotes systemic β-amyloid clearance to mitigate the progression of perioperative neurocognitive disorders in mice

Background: Impaired clearance of beta-amyloid (Aβ) is considered a critical factor contributing to the development of perioperative neurocognitive disorders (PND). Peripheral Aβ clearance has shown promise in reducing brain Aβ levels and preventing PND progression. However, whether peripheral macrophages can mitigate PND-related cognitive impairments and pathological mechanisms remains unclear.

Methods: In this study, we established an animal model of PND using laparotomy. Postoperative cognitive and memory functions in mice were evaluated using the open field test (OFT), fear conditioning test (FCT), and Morris water maze test following intraperitoneal administration of RvD1. Neuro-pathological changes and Aβ levels were assessed using Caspase-3 staining, ELISA, and qRT-PCR. To elucidate the role of FPR2, the receptor for RvD1, in Aβ clearance and inflammation resolution by peripheral macrophages, we conducted protein interaction and enrichment analyses. Additionally, we isolated splenic and peritoneal macrophages directly from tissues and differentiated bone marrow-derived macrophages (BMDMs) in vitro. Phagocytosis, inflammatory markers, and PPARγ pathway activation were analyzed by flow cytometry, Western blotting, and qRT-PCR.

Results: We found that RvD1 treatment reversed surgery-induced cognitive deficits and neuroinflammation in PND mice, primarily through its receptor FPR2. RvD1 facilitated peripheral Aβ clearance, reduced central Aβ deposition, and inhibited neuroinflammation. In Aβ-overexpressing mouse models, RvD1 treatment also activated the STAT6/PPARγ pathway, promoting the anti-inflammatory phenotype of macrophages and significantly reducing Aβ levels in both peripheral and central systems, thereby improving cognitive function. Inhibition of FPR2 or PPARγ abolished the beneficial effects of RvD1, confirming its dependence on these pathways.

Conclusions: Our findings suggest that RvD1-mediated activation of the STAT6/PPARγ pathway in peripheral macrophages plays a pivotal role in systemic Aβ clearance. The anti-inflammatory polarization of peripheral macrophages in PND mice reduced Aβ deposition and inflammatory responses in both peripheral and central compartments, offering valuable insights into the pathogenesis and potential treatment of PND.

Macrophage; Perioperative neurocognitive disorders; RvD1.