[en] 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.
Disciplines :
Neurology
Author, co-author :
HENEKA, Michael ; Department of Neurology, University of Bonn, Germany 53127
Galea, Elena; Department of Anesthesiology, University of Illinois, Chicago, IL 60612, United States
Gavriluyk, Vitaliy; Department of Anesthesiology, University of Illinois, Chicago, IL 60612, United States
Dumitrescu-Ozimek, Lucia; Department of Neurology, University of Bonn, Germany
Daeschner, JoAnna; Dept. of Neurobiology and Anatomy, Univ. of Rochester Medical Center, Rochester, NY 14642, United States
O'Banion, M Kerry; Dept. of Neurobiology and Anatomy, Univ. of Rochester Medical Center, Rochester, NY 14642, United States
Weinberg, Guy; Department of Anesthesiology, University of Illinois, Chicago, IL 60612, United States
Klockgether, Thomas; Department of Neurology, University of Bonn, Germany
Feinstein, Douglas L; Department of Anesthesiology, University of Illinois, Chicago, IL 60612, United States ; Department of Anesthesiology, University of Illinois, MC 519, Chicago, IL 60612, United States
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