Connecting TNF-alpha signaling pathways to iNOS expression in a mouse model of Alzheimer's disease: relevance for the behavioral and synaptic deficits induced by amyloid beta protein.
Increased brain deposition of amyloid beta protein (Abeta) and cognitive deficits are classical signals of Alzheimer's disease (AD) that have been highly associated with inflammatory alterations. The present work was designed to determine the correlation between tumor necrosis factor-alpha (TNF-alpha)-related signaling pathways and inducible nitric oxide synthase (iNOS) expression in a mouse model of AD, by means of both in vivo and in vitro approaches. The intracerebroventricular injection of Abeta(1-40) in mice resulted in marked deficits of learning and memory, according to assessment in the water maze paradigm. This cognition impairment seems to be related to synapse dysfunction and glial cell activation. The pharmacological blockage of either TNF-alpha or iNOS reduced the cognitive deficit evoked by Abeta(1-40) in mice. Similar results were obtained in TNF-alpha receptor 1 and iNOS knock-out mice. Abeta(1-40) administration induced an increase in TNF-alpha expression and oxidative alterations in prefrontal cortex and hippocampus. Likewise, Abeta(1-40) led to activation of both JNK (c-Jun-NH2-terminal kinase)/c-Jun and nuclear factor-kappaB, resulting in iNOS upregulation in both brain structures. The anti-TNF-alpha antibody reduced all of the molecular and biochemical alterations promoted by Abeta(1-40). These results provide new insights in mouse models of AD, revealing TNF-alpha and iNOS as central mediators of Abeta action. These pathways might be targeted for AD drug development.
Medeiros
Rodrigo
R
Departamento de Farmacologia, Centro de Ciências Biológicas, Hospital Universitário-Universidade Federal de Santa Catarina, 88049-900, Florianópolis, Santa Catarina, Brazil.
Prediger
Rui D S
RD
Passos
Giselle F
GF
Pandolfo
Pablo
P
Duarte
Filipe S
FS
Franco
Jeferson L
JL
Dafre
Alcir L
AL
Di Giunta
Gabriella
G
Figueiredo
Cláudia P
CP
Takahashi
Reinaldo N
RN
Campos
Maria M
MM
Calixto
João B
JB
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage* / Q000502:physiology; D000818:Animals; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D007276:Injections, Intraventricular; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
D016229:Amyloid beta-Peptides; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II