Effects of aging on blood brain barrier and matrix metalloproteases following controlled cortical impact in mice

Abstract

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 (21–15 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.

Crocus sativus Extract Tightens the Blood-Brain Barrier, Reduces Amyloid β Load and Related Toxicity in 5XFAD Mice

“…Available evidence suggests that in AD and aging brains have leaky BBB manifested by increased endogenous IgG extravasation to the brain. 36,37 The exact causes for BBB dysfunction in AD are not well-known, however impaired clearance of A β from the brain across the BBB as well as A β ’s role in mediating increases in endothelial cell permeability, 25 have been proposed to enhance accumulation of cerebrovascular and parenchymal amyloid deposits. 38 Immunostaining results demonstrated that Crocus sativus extract significantly reduced IgG extravasation by 47% in 5XFAD mice brains (Figure 6A, P < 0.001), which was associated with increased expression of the tight junction protein cloudin-5 in brain microvessles by 38% (Figure 6B, P < 0.05).…”

Effects of minocycline on spatial learning, hippocampal neurogenesis and microglia in aged and adult mice

“…Animal models of Fragile-x syndrome have indicated that minocycline, through inhibition of MMP-9, improves cognitive function and promotes maturation of dendritic spines in vivo and in vitro [28]. Recent work by Lee et al [29] has shown that MMP-9 levels are elevated in the brain of aged mice compared to adults. Though currently unknown, the age-related increase in MMP-9 may contribute to cognitive deficits that may be attenuated by minocycline treatment.…”

Reperfusion Injury on Magnetic Resonance Imaging After Carotid Revascularization

“…8 Regarding leukoaraiosis, blood-brain barrier disruption and vasogenic edema would be attributable to the pathogenesis of leukoaraiosis. 9 Age is the most important risk factor for leukoaraiosis.…”