Takahiro MASUDA

Neuroimmunology, Neuroscience

Under Moonshot Goal 7: “Brain Senoinflammation”, we are conducting the project titled “Comprehensive analysis of dementia-related pathologies using high-depth multi-omics approaches.” In this research, we employ advanced methodologies such as single-cell spatial transcriptomics, RNA-seq, ATAC-seq, comprehensive lipidomics, and epigenomic analyses to investigate changes in the brain parenchyma and brain boundaries associated with the brain immune system, including glial cells, during aging and chronic inflammation. By visualizing these alterations across multiple scales—from individual cells to intercellular networks, and from brain regions including boundaries to their peripheral interactions—we aim to comprehensively elucidate the molecular, cellular, and tissue-level mechanisms underlying brain functional decline. Furthermore, through this integrative, multi-modal approach, we strive to develop and validate novel strategies for the early detection and intervention of dementia.

Identification of structural changes in the brain parenchyma associated with aging and chronic inflammation using multi-omics analysis

The brain, which is responsible for complex and highly advanced central nervous functions, maintains and regulates its function precisely through bidirectional interactions among various cell types, even while being influenced by numerous external and internal factors. Therefore, to understand the mechanisms underlying brain dysfunction leading to dementia, it is essential to conduct integrative analyses that encompass multidimensional and multiscale information within the brain. To this end, we visualize alterations in the brain parenchyma and brain boundaries—particularly those associated with glial cells and the brain immune system during aging and chronic inflammation—using cutting-edge analytical techniques such as whole-brain clearing and high-depth multi-omics analysis. Through these diverse modalities, we aim to elucidate the mechanisms of brain functional decline at molecular, cellular, and tissue levels.

Elucidation of brain dysfunction mechanisms and development of intervention technologies targeting the brain parenchyma and its boundaries

To deepen our understanding of the pathological mechanisms of dementia, we focus not only on the brain parenchyma but also on the brain boundaries, whose functional significance has recently attracted considerable attention. Our research aims to comprehensively understand the mechanisms of brain dysfunction by analyzing multiple scales—from intercellular interactions among diverse cell types to the relationships between brain regions (including boundaries) and the periphery. Furthermore, we are developing and validating novel intervention technologies that target molecular bases and structural or functional alterations in the brain parenchyma and boundary regions.

Yamamoto S, Masuda T. Lipid in microglial biology – from material to mediator. Inflamm Regen. 43(1):38, 2023. doi: 10.1186/s41232-023-00289-z.

Amann L, Masuda T, Prinz M. Mechanisms of myeloid cell entry to the healthy and diseased central nervous system. Nat Immunol. 24(3):393-407, 2023. doi: 10.1038/s41590-022-01415-8. 

Yamasaki A, Shintaku H, Harada A, Maehara K, Tanaka K, Saeki M, Ito M, Konishi H, Tsuda M, Prinz M, Kishi Y, Ohkawa Y, Yamamoto S, Masuda T. Cyclin-dependent kinase inhibitor 1A mediates mouse line- and fate-dependent cellular responses in Cx3cr1-Cre genetic tools. Cell Rep.44(9):116267, 2025. doi: 10.1016/j.celrep.2025.116267.

Frosch M, Shimizu T, Wogram E, Amann L, Gruber L, Groisman AI, Fliegauf M, Schwabenland M, Chhatbar C, Zechel S, Rosewich H, Gärtner J, Quintana FJ, Buescher JM, Blank T, Binder H, Stadelmann C, Letzkus JJ, Hopf C, Masuda T, Knobeloch KP, Prinz M. Microglia-neuron crosstalk through Hex-MG2-MGL2 mains brain homeostasis. Nature. 646(8086):913-924, 2025. doi: 10.1038/s41586-025-09477-y.

Yamasaki A, Imanishi I, Tanaka K, Ohkawa Y, Tsuda M, Masuda T. IRF8 and MAFB drive distinct transcriptional machineries in different resident macrophages of the central nervous system. Commun Biol. 7(1):896, 2024. doi: 10.1038/s42003-024-06607-6.

Masuda T, Amann L, Monaco G, Sankowski R, Staszewski O, Krueger M, Del Gaudio F, He L, Paterson N, Nent E, Fernández-Klett F, Yamasaki A, Frosch M, Fliegauf M, Bosch LFP, Ulupinar H, Hagemeyer N, Schreiner D, Dorrier C, Tsuda M, Grothe C, Joutel A, Daneman R, Betsholtz C, Lendahl U, Knobeloch KP, Lämmermann T, Priller J, Kierdorf K, Prinz M. Specification of CNS macrophage subsets occurs postnatally in defined niches. Nature. 604(7907):740-748, 2022. doi: 10.1038/s41586-022-04596-2.

Masuda T, Amann L, Sankowski R, Staszewski O, Lenz M, D Errico P, Snaidero N, Costa Jordão MJ, Böttcher C, Kierdorf K, Jung S, Priller J, Misgeld T, Vlachos A, Meyer-Luehmann M, Knobeloch KP, Prinz M. Novel Hexb-based tools for studying microglia in the CNS. Nat Immunol. 21(7):802-815, 2020. doi: 10.1038/s41590-020-0707-4.

Masuda T, Sankowski R, Staszewski O, Böttcher C, Amann L, Sagar, Scheiwe C, Nessler S, Kunz P, van Loo G, Coenen VA, Reinacher PC, Michel A, Sure U, Gold R, Grün D, Priller J, Stadelmann C, Prinz M. Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature. 566(7744):388-392, 2019. doi: 10.1038/s41586-019-0924-x.