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P1‐312: Blocking interleukin‐1 function attenuates Alzheimer's pathology via reducing anti‐inflammatory responses in a transgenic mouse model
Author(s) -
Kitazawa Masashi,
Cheng David,
Tsukamoto Michelle,
Vasilevko Vitaly,
Cribbs David C.,
LaFerla Frank M.
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.865
Subject(s) - genetically modified mouse , downregulation and upregulation , inflammation , medicine , tumor necrosis factor alpha , hippocampus , in vivo , proinflammatory cytokine , interleukin , immunology , cytokine , alzheimer's disease , endocrinology , transgene , disease , biology , biochemistry , gene , microbiology and biotechnology
Background: Inflammation plays an important role in the progression of Alzheimer disease (AD) pathologies. Its effects, however, are dichotomous, and the exact mechanisms of action during the disease progression remain to be elucidated. Epidemiological studies reveal a suppression of inflammation reduces a risk of AD, and clinical data from AD patients show aberrant increases in pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) while marked decreases in anti-inflammatory cytokines in the plasma as well as brain. To support these findings, a large body of in vitro and in vivo studies demonstrated that upregulation of IL-1beta or TNF-alpha exacerbates AD-like pathologies. We previously demonstrated that aberrant upregulation of IL-1beta may mediate AD-like pathologies in 3xTg-AD mice. Methods: Nine-month old 3xTg-AD mice received anti-IL-1 receptor blocking antibody (antiIL-1Rab; 200 micro-g, every 9-10 days) intraperitoneally for 6 months. Sham-treated mice received isotype-matched IgG injection in the same manner, and control mice were untreated throughout the treatment period. Results: Cognitive functions were assessed at the end of the treatment period, and we found that mice with anti-IL-1Rab treatment showed a significantly better cognitive functions than control or sham-treated mice in Morris water maze, novel object recognition and contextual fear conditioning tests. Pathologically, anti-IL-1Rab-treated mice have markedly reduced Abeta plauque burden and hyperphosphorylated tau accumulations in CA1 hippocampus region although quantitative Abeta ELISA analysis revealed a significant increase in soluble Abeta42 species in the brain. Interestingly, levels of oligomeric Abeta species detected by antibodies A11 or OC were significantly reduced by the anti-IL-1Rab treatment. Pro-inflammatory responses in the brain were altered as detected by significant reductions of IL-1beta and TNF-alpha, while increased number of microglia containing 6E10-positive APP fragments was observed in the anti-IL-1Rab-treated mice. Changes in tau phosphorylation was mediated by an inactivation of glycogen synthase kinase-3beta, and cellular catenin signaling was also altered. Conclusions: These data suggest that an inhibition of a specific pro-inflammatory cytokine may modulate the overall brain inflammatory responses as well as the progression of AD-like pathologies. Therefore, targeting specific inflammatory molecules could be beneficial and may help to develop potential therapeutic strategies for AD.