Beta-amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo: involvement of the p38MAPK pathway.
Injection into the nucleus basalis of the rat of preaggregated Abeta(1-42) produced a congophylic deposit and microglial and astrocyte activation and infiltration and caused a strong inflammatory reaction characterized by IL-1beta production, increased inducible cyclooxygenase (COX-2), and inducible nitric oxide synthase (iNOS) expression. Many phospho-p38MAPK-positive cells were observed around the deposit at 7 days after Abeta injection. Phospho-p38MAPK colocalized with activated microglial cells, but not astrocytes. The inflammatory reaction was accompanied by cholinergic hypofunction. We investigated the protective effect of the selective COX-2 inhibitor rofecoxib in attenuating the inflammatory response and neurodegeneration evoked by Abeta(1-42). Rofecoxib (3 mg/kg/day, 7 days) reduced microglia and astrocyte activation, iNOS induction, and p38MAPK activation to control levels. Cholinergic hypofunction was also significantly attenuated by treatment with rofecoxib. We show here for the first time in vivo the pivotal role played by the p38MAPK microglial signal transduction pathway in the inflammatory response to the Abeta(1-42) deposit.
Giovannini
Maria Grazia
MG
Department of Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. mggiov@pharm.unifi.it
Scali
Carla
C
Prosperi
Costanza
C
Bellucci
Arianna
A
Vannucchi
Maria Giuliana
MG
Rosi
Susanna
S
Pepeu
Giancarlo
G
Casamenti
Fiorella
F
D000109:Acetylcholine / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D020532:Basal Nucleus of Meynert / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D002795:Choline O-Acetyltransferase / Q000187:drug effects / Q000378:metabolism; D002799:Cholinergic Fibers / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051546:Cyclooxygenase 2; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004660:Encephalitis / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D005911:Gliosis / Q000139:chemically induced; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000378:metabolism; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases
D016229:Amyloid beta-Peptides; D007375:Interleukin-1; D007527:Isoenzymes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D002795:Choline O-Acetyltransferase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000109:Acetylcholine