title: The blood-brain barrier is disrupted in a mouse model of infantile neuronal ceroid lipofuscinosis: amelioration by resveratrol.
abstract: Disruption of the blood-brain barrier (BBB) is a serious complication frequently encountered in neurodegenerative disorders. Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating childhood neurodegenerative lysosomal storage disorder caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency. It remains unclear whether BBB is disrupted in INCL and if so, what might be the molecular mechanism(s) of this complication. We previously reported that the Ppt1-knockout (Ppt1-KO) mice that mimic INCL manifest high levels of oxidative stress and neuroinflammation. Recently, it has been reported that CD4(+) T-helper 17 (T(H)17) lymphocytes may mediate BBB disruption and neuroinflammation, although the precise molecular mechanism(s) remain unclear. We sought to determine: (i) whether the BBB is disrupted in Ppt1-KO mice, (ii) if so, do T(H)17-lymphocytes underlie this complication, and (iii) how might T(H)17 lymphocytes breach the BBB. Here, we report that the BBB is disrupted in Ppt1-KO mice and that T(H)17 lymphocytes producing IL-17A mediate disruption of the BBB by stimulating production of matrix metalloproteinases (MMPs), which degrade the tight junction proteins essential for maintaining BBB integrity. Importantly, dietary supplementation of resveratrol (RSV), a naturally occurring antioxidant/anti-inflammatory polyphenol, markedly reduced the levels of T(H)17 cells, IL-17A and MMPs, and elevated the levels of tight junction proteins, which improved the BBB integrity in Ppt1-KO mice. Intriguingly, we found that RSV suppressed the differentiation of CD4(+) T lymphocytes to IL-17A-positive T(H)17 cells. Our findings uncover a mechanism by which T(H)17 lymphocytes mediate BBB disruption and suggest that small molecules such as RSV that suppress T(H)17 differentiation are therapeutic targets for neurodegenerative disorders such as INCL.
authors.affiliation: Section on Developmental Genetics, Program on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892-1830, USA.
authors.forename: Arjun
authors.initials: A
authors.lastname: Saha
authors.forename: Chinmoy
authors.initials: C
authors.lastname: Sarkar
authors.forename: Satya P
authors.initials: SP
authors.lastname: Singh
authors.forename: Zhongjian
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jeeva
authors.initials: J
authors.lastname: Munasinghe
authors.forename: Shiyong
authors.initials: S
authors.lastname: Peng
authors.forename: Goutam
authors.initials: G
authors.lastname: Chandra
authors.forename: Eryan
authors.initials: E
authors.lastname: Kong
authors.forename: Anil B
authors.initials: AB
authors.lastname: Mukherjee
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009472:Neuronal Ceroid-Lipofuscinoses / Q000201:enzymology / Q000378:metabolism*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D013869:Thiolester Hydrolases / Q000235:genetics* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D013267:Stilbenes; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase; D000077185:Resveratrol