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The Journal of Neuroscience, April 1, 2002, 22(7):2434-2442
Noradrenergic Depletion Potentiates  -Amyloid-Induced Cortical
Inflammation: Implications for Alzheimer's Disease
Michael T.
Heneka1,
Elena
Galea2,
Vitaliy
Gavriluyk2,
Lucia
Dumitrescu-Ozimek1,
JoAnna
Daeschner3,
M. Kerry
O'Banion3,
Guy
Weinberg2,
Thomas
Klockgether1, and
Douglas L.
Feinstein2
1 Department of Neurology, University of Bonn,
Germany 53127, 2 Department of Anesthesiology, University
of Illinois, Chicago, Illinois 60612, and 3 Department of
Neurobiology and Anatomy, University of Rochester Medical Center,
Rochester, New York 14642
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  (A). 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 A (aggregated 1-42 peptide). DSP4 treatment potentiated the A-dependent induction of inflammatory nitric oxide
synthase (iNOS), interleukin (IL)-1, 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 A induced iNOS primarily in microglial cells, whereas in DSP4-treated animals, iNOS was localized to neurons, as is observed
in AD brains. Injection of A increased IL-1 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-1 expression were
attenuated by coinjection with NE or the -adrenergic receptor agonist isoproterenol. These data demonstrate that LC loss and NE
depletion augment inflammatory responses to A and suggest that LC
loss in AD is permissive for increased inflammation and neuronal cell death.
Key words:
nitric oxide; amyloid; Alzheimer's disease; cytokines; locus ceruleus; interleukin
Copyright © 2002 Society for Neuroscience 0270-6474/02/2272434-09$05.00/0
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