Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease

Jing Ji Jin, Hong Duck Kim, J. Adam Maxwell, Ling Li, Ken Ichiro Fukuchi

Research output: Contribution to journalArticlepeer-review

220 Scopus citations


Background: Aβ deposits in the brains of patients with Alzheimer's disease (AD) are closely associated with innate immune responses such as activated microglia and increased cytokines. Accumulating evidence supports the hypothesis that innate immune/inflammatory responses play a pivotal role in the pathogenesis of AD: either beneficial or harmful effects on the AD progression. The molecular mechanisms by which the innate immune system modulates the AD progression are not well understood. Toll-like receptors (TLRs) are first-line molecules for initiating the innate immune responses. When activated through TLR signaling, microglia respond to pathogens and damaged host cells by secreting chemokines and cytokines and express the co-stimulatory molecules needed for protective immune responses to pathogens and efficient clearance of damaged tissues. We previously demonstrated that an AD mouse model homozygous for a destructive mutation of TLR4 has increases in diffuse and fibrillar Aβ deposits as well as buffer-soluble and insoluble Aβ in the brain as compared with a TLR4 wild-type AD mouse model. Here, we investigated the roles of TLR4 in Aβ-induced upregulation of cytokines and chemokines, Aβ-induced activation of microglia and astrocytes and Aβ-induced immigration of leukocytes. Methods: Using the same model, levels of cytokines and chemokines in the brain were determined by multiplex cytokine/chemokine array. Activation of microglia and astrocytes and immigration of leukocytes were determined by immunoblotting and immunohistochemistry followed by densitometry and morphometry, respectively. Results: Levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-10 and IL-17 in the brains of TLR4 wild-type AD mice were significantly higher than those in TLR4 wild-type non-transgenic littermates. Such increases in cytokines were not found in TLR4 mutant AD mice as compared with TLR4 mutant non-transgenic littermates. Although expression levels of CD11b (a microglia marker) and GFAP (a reactive astrocyte marker) in the brains of TLR4 mutant AD mice were higher than those in TLR4 wild type AD mice, no difference was found in levels of CD45 (common leukocyte antigen). Conclusion: This is the first demonstration of TLR4-dependent upregulation of cytokines in an AD mouse model. Our results suggest that TLR4 signaling is involved in AD progression and that TLR4 signaling can be a new therapeutic target for AD.

Original languageEnglish (US)
Article number23
JournalJournal of Neuroinflammation
StatePublished - May 29 2008

Bibliographical note

Funding Information:
We thank Drs. David Borchelt and Joanna Jankowsky for providing the Mo/ Hu APPsw PS1dE9 mice and Linda Walter for her help with preparing this manuscript. This research is supported in part by NIH AG029818 and EY018478, and Alzheimer's Association IIRG-07-59494 and NIRG-06-27725.


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