PMID- 23867621
OWN - NLM
STAT- MEDLINE
DCOM- 20131022
LR  - 20211021
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 123
IP  - 8
DP  - 2013 Aug
TI  - Cerebrovascular degradation of TRKB by MMP9 in the diabetic brain.
PG  - 3373-7
LID - 65767 [pii]
LID - 10.1172/JCI65767 [doi]
AB  - 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.
FAU - Navaratna, Deepti
AU  - Navaratna D
AD  - Neuroprotection Research Laboratory, Departments of Radiology, Neurology, and 
      Pediatrics, Massachusetts General Hospital, Harvard Medical School, Charlestown, 
      Massachusetts 02129, USA. deeptinavaratna@gmail.com
FAU - Fan, Xiang
AU  - Fan X
FAU - Leung, Wendy
AU  - Leung W
FAU - Lok, Josephine
AU  - Lok J
FAU - Guo, Shuzhen
AU  - Guo S
FAU - Xing, Changhong
AU  - Xing C
FAU - Wang, Xiaoying
AU  - Wang X
FAU - Lo, Eng H
AU  - Lo EH
LA  - eng
GR  - R01 NS076694/NS/NINDS NIH HHS/United States
GR  - K08 NS057339/NS/NINDS NIH HHS/United States
GR  - RC2-NS69335/NS/NINDS NIH HHS/United States
GR  - R01-NS76694/NS/NINDS NIH HHS/United States
GR  - P01-NS55104/NS/NINDS NIH HHS/United States
GR  - P01 NS055104/NS/NINDS NIH HHS/United States
GR  - RC2 NS069335/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130715
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - EC 3.4.24.35 (Mmp9 protein, rat)
SB  - IM
MH  - Animals
MH  - Brain/blood supply/*enzymology
MH  - Cells, Cultured
MH  - Diabetes Mellitus, Experimental/*enzymology
MH  - Endothelial Cells/enzymology
MH  - Enzyme Induction
MH  - Humans
MH  - Matrix Metalloproteinase 9/chemistry/genetics/*metabolism
MH  - Microvessels/pathology
MH  - Primary Cell Culture
MH  - Proteolysis
MH  - Rats
MH  - Receptor, trkB/chemistry/*metabolism
MH  - Up-Regulation
PMC - PMC3726155
EDAT- 2013/07/23 06:00
MHDA- 2013/10/23 06:00
PMCR- 2013/07/15
CRDT- 2013/07/23 06:00
PHST- 2012/07/11 00:00 [received]
PHST- 2013/05/16 00:00 [accepted]
PHST- 2013/07/23 06:00 [entrez]
PHST- 2013/07/23 06:00 [pubmed]
PHST- 2013/10/23 06:00 [medline]
PHST- 2013/07/15 00:00 [pmc-release]
AID - 65767 [pii]
AID - 10.1172/JCI65767 [doi]
PST - ppublish
SO  - J Clin Invest. 2013 Aug;123(8):3373-7. doi: 10.1172/JCI65767. Epub 2013 Jul 15.