ADAMTS18 deficiency leads to abnormal brain methylation metabolism, dysregulated neuroinflammatory response, and unsound blood-brain barrier structure in mice

ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family is a group of secretory proteases involved in the maintenance of central nervous system (CNS) homeostasis and neuronal disease. ADAMTS18 is a member of this family and has been linked to the integrity of the human brain’s white matter. However, the cellular and molecular basis of ADAMTS18 in brain metabolism and homeostasis remains unclear. In this study, a total of 47,719 genes were identified in 8 independent wild type (WT) and Adamts18 knockout (KO) mouse brain samples using brain transcriptomic analysis. The abundance of 100 genes in brain was significantly different between WT and KO mice. ADAMTS18 deficiency resulted in decreased S-adenosine homocysteine hydrolase (SAHH) levels, impaired brain methyl cycle metabolism and dysregulation of neuroinflammatory-related factors (e.g., Lrg1, and Lcn2) in mouse brain. The number and branching complexity of microglia in brain tissue of Adamts18 KO mice were significantly reduced. Adamts18 KO mice also showed poor blood-brain barrier (BBB) integrity. Mechanically, ADAMTS18 deficiency resulted in significant downregulation of Il- 34, Csf1r, Cx3cl1, Cx3cr1, Fn, Tgfb1, Tgfbr2, Smad4 and Sall1 genes related to microglia expansion, migration, characteristic development and maintenance. BBB integrity related markers Glut1, Plvap, Zo- 1, Occludin or Aqp- 4 were partially dysregulated in the brain tissue of Adamts18 KO mice and significantly deteriorated after LPS stimulation. Collectively, these results shed light on the significance of ADAMTS18 in brain methyl cycle metabolism, neuroinflammatory regulation and BBB structure maintenance.