title: Noradrenergic depletion potentiates beta -amyloid-induced cortical inflammation: implications for Alzheimer's disease.
abstract: Degeneration of locus ceruleus (LC) neurons and reduced levels of norepinephrine (NE) in LC projection areas are well known features of Alzheimer's disease (AD); however, the consequences of those losses are not clear. Because inflammatory mediators contribute to AD pathogenesis and because NE can suppress inflammatory gene expression, we tested whether LC loss influenced the brain inflammatory gene expression elicited by amyloid beta (Abeta). Adult rats were injected with the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP4) to induce LC death and subsequently injected in the cortex with Abeta (aggregated 1-42 peptide). DSP4 treatment potentiated the Abeta-dependent induction of inflammatory nitric oxide synthase (iNOS), interleukin (IL)-1beta, and IL-6 expression compared with control animals. In contrast, the induction of cyclooxygenase-2 expression was not modified by DSP4 treatment. In control animals, injection of Abeta induced iNOS primarily in microglial cells, whereas in DSP4-treated animals, iNOS was localized to neurons, as is observed in AD brains. Injection of Abeta increased IL-1beta expression initially in microglia and at later times in astrocytes, and expression levels were greater in DSP4-treated animals than in controls. The potentiating effects of DSP4 treatment on iNOS and IL-1beta expression were attenuated by coinjection with NE or the beta-adrenergic receptor agonist isoproterenol. These data demonstrate that LC loss and NE depletion augment inflammatory responses to Abeta and suggest that LC loss in AD is permissive for increased inflammation and neuronal cell death.
authors.affiliation: Department of Neurology, University of Bonn, Germany 53127.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.forename: Elena
authors.initials: E
authors.lastname: Galea
authors.forename: Vitaliy
authors.initials: V
authors.lastname: Gavriluyk
authors.forename: Lucia
authors.initials: L
authors.lastname: Dumitrescu-Ozimek
authors.forename: JoAnna
authors.initials: J
authors.lastname: Daeschner
authors.forename: M Kerry
authors.initials: MK
authors.lastname: O'Banion
authors.forename: Guy
authors.initials: G
authors.lastname: Weinberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Klockgether
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Feinstein
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000544:Alzheimer Disease / Q000209:etiology* / Q000276:immunology; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage / Q000633:toxicity; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D004333:Drug Administration Routes; D004357:Drug Synergism; D004660:Encephalitis / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D008125:Locus Coeruleus / Q000187:drug effects / Q000473:pathology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009638:Norepinephrine / Q000008:administration & dosage / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis
chemical_list: D000276:Adjuvants, Immunologic; D000318:Adrenergic beta-Agonists; D016229:Amyloid beta-Peptides; D001596:Benzylamines; D007375:Interleukin-1; D010446:Peptide Fragments; D012333:RNA, Messenger; C075222:amyloid beta-protein (1-42); D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D014446:Tyrosine 3-Monooxygenase; C012102:DSP 4; D009638:Norepinephrine