Effects of aging on blood brain barrier and matrix metalloproteases following controlled cortical impact in mice.
Aging alters the ability of the brain to respond to injury. One of the major differences between the adult and aged brain is that comparable injuries lead to greater blood brain barrier disruption in the aged brain. The goals of these studies were to quantify the effects of age on BBB permeability using high field strength MRI T1 mapping and to determine whether activation of matrix metalloproteases, their inhibitors, or expression of blood brain barrier structural proteins, occludin, zonnula occludins-1 (ZO-1) and claudin-5 were altered following injury to the aged C57/BL6 mouse brain. T1 mapping studies revealed greater blood brain barrier permeability in the aged (21-24 months old) brain than in the adult (4-6 months old) following controlled cortical impact. The increased blood brain barrier permeability in the pericontusional region was confirmed with IgG immunohistochemistry. MMP-9 activity was increased following controlled cortical impact in the aged brain, and this was accompanied by increased MMP-9 gene expression. MMP-2 activity was higher in the uninjured aged brain than in the adult brain. Occludin and ZO-1 mRNA levels were unchanged following injury in either age group, but claudin-5 mRNA levels were lower in the aged than the adult brain following injury. These results demonstrate quantitative increases in blood brain barrier permeability in the aged brain following injury that are accompanied by increased MMP-9 activation and decreased blood brain barrier repair responses.
Hoglund Brain Imaging Center, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
Phil
P
Lee
Jieun
J
Kim
Rachel
R
Williams
Rajat
R
Sandhir
Eugene
E
Gregory
William M
WM
Brooks
Nancy E J
NE
Berman
D000375:Aging; D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001930:Brain Injuries / Q000201:enzymology* / Q000473:pathology*; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000473:pathology*; D004195:Disease Models, Animal; D019786:Gadolinium DTPA; D005786:Gene Expression Regulation / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D062793:Occludin; D010539:Permeability; D010750:Phosphoproteins / Q000378:metabolism; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D015599:Trauma Severity Indices; D062826:Zonula Occludens-1 Protein
D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; D010750:Phosphoproteins; D019714:Tissue Inhibitor of Metalloproteinases; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D019786:Gadolinium DTPA