Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease.
BACKGROUND
Abeta 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 Abeta deposits as well as buffer-soluble and insoluble Abeta in the brain as compared with a TLR4 wild-type AD mouse model. Here, we investigated the roles of TLR4 in Abeta-induced upregulation of cytokines and chemokines, Abeta-induced activation of microglia and astrocytes and Abeta-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)-alpha, interleukin (IL)-1beta, 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).


CONCLUSIONS
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.
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Box 1649, Peoria, IL 61656, USA. jingji@uic.edu
Jing-Ji
JJ
Jin
Hong-Duck
HD
Kim
J Adam
JA
Maxwell
Ling
L
Li
Ken-Ichiro
K
Fukuchi
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002540:Cerebral Cortex / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D017354:Point Mutation; D053764:Presenilin-1 / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D017384:Sequence Deletion; D013047:Specific Pathogen-Free Organisms; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; D020381:Interleukin-17; D053583:Interleukin-1beta; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011993:Recombinant Fusion Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10