Endogenous brain cytokine mRNA and inflammatory responses to lipopolysaccharide are elevated in the Tg2576 transgenic mouse model of Alzheimer's disease.
Beta-amyloid (Abeta) plaques have been shown to induce inflammatory changes in Alzheimer's disease brains. Cortical, but not cerebellar tissue from 16-month-old Tg2576 (Tg+) mice showed significant increases in interleukin (IL)-1alpha (2.2-fold), IL-1beta (3.4-fold), tumor necrosis factor-alpha (3.9-fold), and monocyte chemoattractant protein-1 (2.5-fold) mRNA levels compared to controls (Tg-). These changes were not apparent in 6-month-old Tg+ mice except for TNF-alpha. mRNA levels of glial fibrillary acidic protein and complement components, C1qA and C3 were also elevated in aged mice. Lipopolysaccharide (LPS) (25 microg/mouse, i.v.) induced a significantly greater production of IL-1beta protein in the cortices and hippocampi of Tg+ vs. Tg- mice at 1, 2, 4, and 6 h. Experiments in 6-month-old mice showed that not only was there less cytokine produced compared to 16-month-old mice, but the exacerbated cytokine response to LPS in Tg+ mice was not apparent. Higher levels of Abeta1-40 were measured in the cortices of 6- and 16-month-old Tg+ mice at 4-6 h after LPS, which returned to baseline after 18 h. We demonstrate that Abeta plaques elicit inflammatory responses in Tg2576 mice that are further exacerbated when challenged by an exogenous inflammatory insult, which may serve to amplify degenerative processes.
Sly
L M
LM
Pharmacology, Pharmacia Corp, Kalamazoo, MI 49007, USA
Krzesicki
R F
RF
Brashler
J R
JR
Buhl
A E
AE
McKinley
D D
DD
Carter
D B
DB
Chin
J E
JE
D000375:Aging / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics; D016207:Cytokines / Q000235:genetics*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics; D008297:Male; D051379:Mice; D058225:Plaque, Amyloid / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D016229:Amyloid beta-Peptides; D018932:Chemokine CCL2; D016207:Cytokines; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha