title: Cerebrovascular degradation of TRKB by MMP9 in the diabetic brain.
abstract: Diabetes elevates the risk for neurological diseases, but little is known about the underlying mechanisms. Brain-derived neurotrophic factor (BDNF) is secreted by microvascular endothelial cells (ECs) in the brain, functioning as a neuroprotectant through the activation of the neurotrophic tyrosine kinase receptor TRKB. In a rat model of streptozotocin-induced hyperglycemia, we found that endothelial activation of MMP9 altered TRKB-dependent trophic pathways by degrading TRKB in neurons. Treatment of brain microvascular ECs with advanced glycation endproducts (AGE), a metabolite commonly elevated in diabetic patients, increased MMP9 activation, similar to in vivo findings. Recombinant human MMP9 degraded the TRKB ectodomain in primary neuronal cultures, suggesting that TRKB could be a substrate for MMP9 proteolysis. Consequently, AGE-conditioned endothelial media with elevated MMP9 activity degraded the TRKB ectodomain and simultaneously disrupted the ability of endothelium to protect neurons against hypoxic injury. Our findings demonstrate that neuronal TRKB trophic function is ablated by MMP9-mediated degradation in the diabetic brain, disrupting cerebrovascular trophic coupling and leaving the brain vulnerable to injury.
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology, Neurology, and Pediatrics, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. deeptinavaratna@gmail.com
authors.forename: Deepti
authors.initials: D
authors.lastname: Navaratna
authors.forename: Xiang
authors.initials: X
authors.lastname: Fan
authors.forename: Wendy
authors.initials: W
authors.lastname: Leung
authors.forename: Josephine
authors.initials: J
authors.lastname: Lok
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Guo
authors.forename: Changhong
authors.initials: C
authors.lastname: Xing
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000201:enzymology*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D042783:Endothelial Cells / Q000201:enzymology; D004790:Enzyme Induction; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055806:Microvessels / Q000473:pathology; D061251:Primary Cell Culture; D059748:Proteolysis; D051381:Rats; D020813:Receptor, trkB / Q000737:chemistry / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D020813:Receptor, trkB; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat