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How blood brain barrier is breached in a mouse model of INCL
Author(s) -
SAHA ARJUN,
Munasinghe Jeeva,
Zhang Zhongjian,
Heffer Alison,
Mukherjee Anil B
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.590.13
Subject(s) - blood–brain barrier , matrix metalloproteinase , chemistry , knockout mouse , neuroinflammation , parenchyma , microbiology and biotechnology , immunology , biology , endocrinology , pathology , inflammation , medicine , central nervous system , biochemistry , gene
Infantile neuronal ceroid lipofuscinosis (INCL), a devastating neurodegenerative storage disorder of childhood, is caused by mutations in the palmitoyl‐protein thioesterase‐1 ( Ppt1 ) gene. Using a mouse model of INCL, Ppt1 ‐knockout ( Ppt1 ‐KO) mice, we recently reported elevated levels of pro‐inflammatory cytokines such as MCP1, IL‐1β, IL‐6 and TNFα. Since many of these parameters are associated with disruption of the blood brain barrier (BBB), we sought to determine: ( a ) whether BBB is disrupted in the Ppt1 ‐KO mice and if so, ( b ) what might be the molecular mechanism(s). Magnetic Resonance Imaging results showed that while in the 6‐month old Ppt1 ‐KO mice gadolinium (Gd, a contrast medium) readily infiltrated the brain parenchyma, such infiltration was not detectable in the WT mice indicating the BBB disruption in the Ppt1 ‐KO mice. We also found decreased levels of various tight‐junction proteins in the brain tissues of the Ppt1 ‐KO mice. A significantly higher level of IL‐17 as well as T H 17 positive cells were found in the brain of the Ppt1 ‐KO mice. Moreover, the levels of activated matrix metalloproteinases (MMPs), which adversely affect the BBB, are significantly higher in the Ppt1 ‐KO mouse brain. Treatment of cultured glial cells with IL‐17 in vitro appears to stimulate MMPs expression. We propose that T H 17‐mediated activation of matrix metalloproteinases disrupts the BBB contributing to INCL pathogenesis.