Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration.
Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson's disease, but the mechanisms are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNFalpha, 0.25 mg/kg, i.p.) injection was administered in adult wild-type mice and in mice lacking TNFalpha receptors (TNF R1/R2(-/-)) to discern the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences. Systemic LPS administration resulted in rapid brain TNFalpha increase that remained elevated for 10 months, while peripheral TNFalpha (serum and liver) had subsided by 9 h (serum) and 1 week (liver). Systemic TNFalpha and LPS administration activated microglia and increased expression of brain pro-inflammatory factors (i.e., TNFalpha, MCP-1, IL-1beta, and NF-kappaB p65) in wild-type mice, but not in TNF R1/R2(-/-) mice. Further, LPS reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (SN) by 23% at 7-months post-treatment, which progressed to 47% at 10 months. Together, these data demonstrate that through TNFalpha, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated pro-inflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease.
Qin
Liya
L
Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Wu
Xuefei
X
Block
Michelle L
ML
Liu
Yuxin
Y
Breese
George R
GR
Hong
Jau-Shyong
JS
Knapp
Darin J
DJ
Crews
Fulton T
FT
D000818:Animals; D001921:Brain / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016923:Cell Death / Q000276:immunology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology*; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D010300:Parkinson Disease / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D013378:Substantia Nigra / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D004298:Dopamine