Hyo Min Kim¹, Shinheun Kim^2,3, Jueun Sim⁴, Boo Soo Ma⁵, Insung Yong¹, Youngmin Jo¹, Taek-Soo Kim⁵, Jae-Byum Chang⁴, Sung-Hye Park⁶, Yong Jeong^2,7,8, Pilnam Kim^1,7

¹Biological Microenvironment Engineering Laboratory, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
²Laboratory for Cognitive Neuroscience and NeuroImaging, Program of Brain and Cognitive Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
³Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, Korea
⁴Jae-Byum Chang Laboratory, Department of Materials Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
⁵Advanced Packaging and Thin Film Laboratory, Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
⁶Neuroscience Research Institute, Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
⁷KI for Health Science and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
⁸Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea

H.M.K. and S.K. contributed equally to this work.
Correspondence: Pilnam Kim

Collagen is a prominent target of nonenzymatic glycation, which is a hallmark of aging and causes functional alteration of the matrix. Here, we uncover glycation-mediated structural and functional changes in the collagen-enriched meningeal membrane of the human and mouse brain. Using an in vitro culture platform mimicking the meningeal membrane composed of fibrillar collagen, we showed that the accumulation of advanced glycation end products (AGEs) in the collagen membrane is responsible for glycation-mediated matrix remodeling. These changes influence fibroblast-matrix interactions, inducing cell-mediated ECM remodeling. The adherence of meningeal fibroblasts to the glycated collagen membrane was mediated by the discoidin domain-containing receptor 2 (DDR2), whereas integrin-mediated adhesion was inhibited. A-kinase anchoring protein 12 (AKAP12)-positive meningeal fibroblasts in the meningeal membrane of aged mice exhibited substantially increased expression of DDR2 and depletion of integrin beta-1 (ITGB1). In the glycated collagen membrane, meningeal fibroblasts increased the expression of matrix metalloproteinase 14 (MMP14) and less tissue inhibitor of metalloproteinase-1 (TIMP1). In contrast, the cells exhibited decreased expression of type I collagen (COL1A1). These results suggest that glycation modification by meningeal fibroblasts is intimately linked to aging-related structural and functional alterations in the meningeal membrane.