| First Author | Yang Y | Year | 2023 |
| Journal | Brain Behav Immun | Volume | 113 |
| Pages | 228-247 | PubMed ID | 37437821 |
| Mgi Jnum | J:339354 | Mgi Id | MGI:7517916 |
| Doi | 10.1016/j.bbi.2023.07.006 | Citation | Yang Y, et al. (2023) LPS priming before plaque deposition impedes microglial activation and restrains Abeta pathology in the 5xFAD mouse model of Alzheimer's disease. Brain Behav Immun 113:228-247 |
| abstractText | Microglia have an innate immunity memory (IIM) with divergent functions in different animal models of neurodegenerative diseases, including Alzheimer's disease (AD). AD is characterized by chronic neuroinflammation, neurodegeneration, tau tangles and beta-amyloid (Abeta) deposition. Systemic inflammation has been implicated in contributing to the progression of AD. Multiple reports have demonstrated unique microglial signatures in AD mouse models and patients. However, the proteomic profiles of microglia modified by IIM have not been well-documented in an AD model. Therefore, in the present study, we investigate whether lipopolysaccharide (LPS)-induced IIM in the pre-clinical stage of AD alters the microglial responses and shapes the neuropathology. We accomplished this by priming 5xFAD and wild-type (WT) mice with an LPS injection at 6 weeks (before the robust development of plaques). 140 days later, we evaluated microglial morphology, activation, the microglial barrier around Abeta, and Abeta deposition in both 5xFAD primed and unprimed mice. Priming induced decreased soma size of microglia and reduced colocalization of PSD95 and Synaptophysin in the retrosplenial cortex. Priming appeared to increase phagocytosis of Abeta, resulting in fewer Thioflavin S(+) Abeta fibrils in the dentate gyrus. RIPA-soluble Abeta 40 and 42 were significantly reduced in Primed-5xFAD mice leading to a smaller size of MOAB2(+) Abeta plaques in the prefrontal cortex. We also found that Abeta-associated microglia in the Primed-5xFAD mice were less activated and fewer in number. After priming, we also observed improved memory performance in 5xFAD. To further elucidate the molecular mechanism underlying these changes, we performed quantitative proteomic analysis of microglia and bone marrow monocytes. A specific pattern in the microglial proteome was revealed in primed 5xFAD mice. These results suggest that the imprint signatures of primed microglia display a distinctive phenotype and highlight the potential for a beneficial adaption of microglia when intervention occurs in the pre-clinical stage of AD. |
