Lu N, Moran-Losada P, Hahn O, Saksena A, Tapp E, Chadarevian JP, Dong W, Shi SM, Shuken SR, Guldner I, Zeng W, To N-S, Wong PS, Hasselmann J, Davtyan H, Sun J, Li L, Luo J, Yang AC, Li Q, Cheung TH, Abu-Remaileh M, Blurton-Jones M, Wyss-Coray T. Circulatory proteins shape microglia state and boost phagocytosis. 2024 Oct 02 10.1101/2024.09.30.615861 (version 1) bioRxiv.
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German Center for Neurodegenerative Diseases (DZNE)
This new study by Lu and colleagues is an exciting new addition to the field of microglial signalling and regulation, particularly in how messengers from the blood can communicate with brain-resident immune cells.
This paper builds on previous work from the Wyss-Coray group, who showed that plasma proteins can pass into the parenchyma under healthy conditions (Yang et al., 2020), and they now address how such proteins may be affecting the local environment. To do so, Lu and colleagues fluorescently labelled the plasma from mice, injected it i.v. to recipient mice and 20 hours later, examined which microglial populations had taken up the tagged-plasma proteins. Interestingly, the microglial populations that took up the labelled plasma varied considerably by brain region, with hypothalamic microglia taking up the most. RNA sequencing on the plasma-positive versus plasma-negative microglia from the hypothalamus revealed a significant effect of plasma on the microglial transcriptome, with over 500 genes increased in the plasma-positive microglial cells, many relating to innate immune pathways and antigen presentation.
Proteomic analysis of the plasma-positive microglia identified over 200 proteins enriched in these cells, with an overlap between the RNA and protein levels of numerous targets. At a functional level, the plasma-positive microglia were more metabolically active, with increased phagocytic activity, demonstrating how functionally distinct this cellular population was. Via a range of confirmation experiments, Lu and colleagues found that the plasma protein Apolipoprotein A-I (ApoA-I) was taken up by microglia in vivo. Importantly, ApoA-I alone could drive many of the changes induced by bulk plasma, including increasing genes that were identified in the original screen and ApoA-I could regulate microglial function including increasing phagocytosis.
This exciting work highlights the complex signalling occurring between the periphery and the brain, which is an understudied area of research. As the experiments were conducted in young mice, it raises the question of how such processes might change with age and in disease models. Indeed, Lu and colleagues found that the microglia of aged mice took up less labelled-plasma than their young counterparts, and, since these proteins could regulate phagocytosis it may partly explain why microglial phagocytic activity is altered with age (Antignano et al., 2023). It would certainly be interesting to examine whether this pathway is further modulated in neurodegenerative diseases, such as Alzheimer’s, where impaired microglial phagocytosis plays an important role (Podleśny-Drabiniok et al., 2020). As the findings were similar between human and murine microglia, it is interesting to speculate whether ApoA-I administration could have therapeutic benefits to those with neurodegenerative diseases, where successful treatments to stop disease progression are lacking.
ApoA-I is primarily produced by the intestine and liver, therefore future studies could examine how ApoA-I can act as a messenger to the brain during liver or intestinal diseases such as steatotic liver disease or Crohn’s disease. It is likely that in these diseases the circulating plasma proteins are different to basal healthy conditions, which in turn may modulate the microglia and other brain cells in unknown ways. Altogether this important work brings new light to the complex interplay between the periphery and the brain, with the scope to build on these compelling findings to examine these interactions beyond microglia to other brain cells and to better understand these processes in health and disease.
References:
Yang AC, Stevens MY, Chen MB, Lee DP, Stähli D, Gate D, Contrepois K, Chen W, Iram T, Zhang L, Vest RT, Chaney A, Lehallier B, Olsson N, du Bois H, Hsieh R, Cropper HC, Berdnik D, Li L, Wang EY, Traber GM, Bertozzi CR, Luo J, Snyder MP, Elias JE, Quake SR, James ML, Wyss-Coray T. Physiological blood-brain transport is impaired with age by a shift in transcytosis. Nature. 2020 Jul 1; PubMed.
Antignano I, Liu Y, Offermann N, Capasso M. Aging microglia. Cell Mol Life Sci. 2023 Apr 21;80(5):126. PubMed.
Podleśny-Drabiniok A, Marcora E, Goate AM. Microglial Phagocytosis: A Disease-Associated Process Emerging from Alzheimer's Disease Genetics. Trends Neurosci. 2020 Dec;43(12):965-979. Epub 2020 Oct 27 PubMed.
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