[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 :
Neurologie
Auteur, co-auteur :
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
Adolfsson R, Gottfries CG, Roos BE, Winblad B (1979) Changes in the brain catecholamines in patients with dementia of Alzheimer type. Br J Psychiatry 135:216-223.
Akama KT, Van Eldik LJ (2000) Beta-amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-1. J Biol Chem 275:7918-7924.
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, et al (2000) Inflammation and Alzheimer's disease. Neurobiol Aging 21:383-421.
Anlezark GM, Crow TJ, Greenway AP (1973) Impaired learning and decreased cortical norepinephrine after bilateral locus coeruleus lesions. Science 181:682-684.
Apelt J, Schliebs R (2001) Beta-amyloid-induced glial expression of both pro- and anti-inflammatory cytokines in cerebral cortex of aged transgenic Tg2576 mice with Alzheimer plaque pathology. Brain Res 894:21-30.
Bondareff W, Mountjoy CQ, Roth M, Rossor MN, Iversen LL, Reynolds GP, Hauser DL (1987) Neuronal degeneration in locus ceruleus and cortical correlates of Alzheimer disease. Alzheimer Dis Assoc Disord 1:256-262.
Chang JY, Liu LZ (2000) Catecholamines inhibit microglial nitric oxide production. Brain Res Bull 52:525-530.
Feinstein DL (1998) Suppression of astroglial nitric oxide synthase expression by norepinephrine results from decreased NOS-2 promoter activity. J Neurochem 70:1484-1496.
Feinstein DL, Heneka MT, Gavrilyuk V, Dello Russo C, Weinberg G, Galea E (2001) Noradrenergic regulation of inflammatory gene expression in brain. Neurochem Int, in press.
Foote SL, Bloom FE, Aston-Jones G (1983) Nucleus locus ceruleus: new evidence of anatomical and physiological specificity. Physiol Rev 63:844-914.
Forno LS (1992) Neuropathologic features of Parkinson's, Huntington's, and Alzheimer's diseases. Ann NY Acad Sci 648:6-16.
Freedman R, Foote SL, Bloom FE (1975) Histochemical characterization of a neocortical projection of the nucleus locus coeruleus in the squirrel monkey. J Comp Neurol 164:209-231.
Fritschy JM, Grzanna R (1991) Experimentally-induced neuron loss in the locus coeruleus of adult rats. Exp Neurol 111:123-127.
Frohman EM, Vayuvegula B, van den NS, Gupta S (1988) Norepinephrine inhibits gamma-interferon-induced MHC class II (Ia) antigen expression on cultured brain astrocytes. J Neuroimmunol 17:89-101.
Galea E, Feinstein DL (1999) Regulation of the expression of the inflammatory nitric oxide synthase (NOS2) by cyclic AMP. FASEB J 13:2125-2137.
German DC, Manaye KF, White III CL, Woodward DJ, McIntire DD, Smith WK, Kalaria RN, Mann DM (1992) Disease-specific patterns of locus coeruleus cell loss. Ann Neurol 32:667-676.
Harro J, Pahkla R, Modiri A-R, Harro M, Kask A, Oreland L (1999) Dose-dependent effects of noradrenergic denervation by DSP-4 treatment on forced swimming and beta-adrenoceptor binding in the rat. J Neural Transm 106:619-629.
Heneka MT, Feinstein DL, Galea E, Gleichmann M, Wullner U, Klockgether T (1999a) Peroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase. J Neuroimmunol 100:156-168.
Heneka MT, Schmidlin A, Wiesinger H (1999b) Induction of arginino-succinate synthetase in rat brain glial cells after striatal microinjection of immunostimulants. J Cereb Blood Flow Metab 19:898-907.
Heneka MT, Klockgether T, Feinstein DL (2000) Peroxisome proliferator-activated receptor-γ ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo. J Neurosci 20:6862-6867.
Heneka MT, Wiesinger H, Dumitrescu-Ozimek L, Riederer P, Feinstein DL, Klockgether T (2001) Neuronal and glial coexpression of argininosuccinate synthetase and inducible nitric oxide synthase in Alzheimer disease. J Neuropathol Exp Neurol 60:906-916.
Hu J, Van Eldik LJ (1999) Glial-derived proteins activate cultured astrocytes and enhance beta amyloid-induced glial activation. Brain Res 842:46-54.
Hu XX, Goldmuntz EA, Brosnan CF (1991) The effect of norepinephrine on endotoxin-mediated macrophage activation. J Neuroimmunol 31:35-42.
Iversen LL, Rossor MN, Reynolds GP, Hills R, Roth M, Mountjoy CQ, Foote SL, Morrison JH, Bloom FE (1983) Loss of pigmented dopamine-beta-hydroxylase positive cells from locus coeruleus in senile dementia of Alzheimer's type. Neurosci Lett 39:95-100.
Kalaria RN, Stockmeier CA, Harik SI (1989a) Brain microvessels are innervated by locus ceruleus noradrenergic neurons. Neurosci Lett 97:203-208.
Kalaria RN, Andorn AC, Tabaton M, Whitehouse PJ, Harik SI, Unnerstall JR (1989b) Adrenergic receptors in aging and Alzheimer's disease: increased beta 2-receptors in prefrontal cortex and hippocampus. J Neurochem 53:1772-1781.
Lee SC, Collins M, Vanguri P, Shin ML (1992) Glutamate differentially inhibits the expression of class II MHC antigens on astrocytes and microglia. J Immunol 148:3391-3397.
Lee SC, Zhao ML, Hirano A, Dickson DW (1999) Inducible nitric oxide synthase immunoreactivity in the Alzheimer disease hippocampus: association with Hirano bodies, neurofibrillary tangles, and senile plaques. J Neuropathol Exp Neurol 58:1163-1169.
Lee SJ, Drabik K, Van Wagoner NJ, Lee S, Choi C, Dong Y, Benveniste EN (2000) ICAM-1-induced expression of proinflammatory cytokines in astrocytes: involvement of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways. J Immunol 165:4658-4666.
Levine ES, Litto WJ, Jacobs BL (1990) Activity of cat locus coeruleus noradrenergic neurons during the defense reaction. Brain Res 531:189-195.
Licinio J, Prolo P, McCann SM, Wong ML (1999) Brain iNOS: current understanding and clinical implications. Mol Med Today 5:225-232.
Loughlin AJ, Woodroofe MN, Cuzner ML (1993) Modulation of interferon-gamma-induced major histocompatibility complex class II and Fc receptor expression on isolated microglia by transforming growth factor-beta 1, interleukin-4, noradrenaline and glucocorticoids. Immunology 79:125-130.
Mann DM, Yates PO, Hawkes J (1982) The noradrenergic system in Alzheimer and multi-infarct dementias. J Neurol Neurosurg Psychiatry 45:113-119.
Mann DM, Yates PO, Hawkes J (1983) The pathology of the human locus ceruleus. Clin Neuropathol 2:1-7.
Marcyniuk B, Mann DM, Yates PO (1986) Loss of nerve cells from locus coeruleus in Alzheimer's disease is topographically arranged. Neurosci Lett 64:247-252.
Mason ST, Iversen SD (1975) Learning in the absence of forebrain noradrenaline. Nature 258:422-424.
Mavridis M, Degryse AD, Lategan AJ, Marien MR, Colpaert FC (1991) Effects of locus coeruleus lesions on parkinsonian signs, striatal dopamine and substantia nigra cell loss after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in monkeys: a possible role for the locus coeruleus in the progression of Parkinson's disease. Neuroscience 41:507-523.
Mehlhorn G, Hollborn M, Schliebs R (2000) Induction of cytokines in glial cells surrounding cortical beta-amyloid plaques in transgenic Tg2576 mice with Alzheimer pathology. Int J Dev Neurosci 18:423-431.
Mrak RE, Sheng JG, Griffin WS (1995) Glial cytokines in Alzheimer's disease: review and pathogenic implications. Hum Pathol 26:816-823.
Nishino K, Lin CS, Morse JK, Davis JN (1991) DSP4 treatment worsens hippocampal pyramidal cell damage after transient ischemia. Neuroscience 43:361-367.
Paspalas CD, Papadopoulos GC (1998) Ultrastructural evidence for combined action of noradrenaline and vasoactive intestinal polypeptide upon neurons, astrocytes, and blood vessels of the rat cerebral cortex. Brain Res Bull 45:247-259.
Paxinos G, Watson C, Pennisi M, Topple A (1985) Bregma, lambda and the interaural midpoint in stereotaxic surgery with rats of different sex, strain and weight. J Neurosci Methods 13:139-143.
Scheibel AB, Duong TH, Tomiyasu U (1987) Denervation microangiopathy in senile dementia, Alzheimer type. Alzheimer Dis Assoc Disord 1:19-37.
Seguela P, Watkins KC, Geffard M, Descarries L (1990) Noradrenaline axon terminals in adult rat neocortex: an immunocytochemical analysis in serial thin sections. Neuroscience 35:249-264.
Sheng JG, Jones RA, Zhou XQ, McGinness JM, Van Eldik LJ, Mrak RE, Griffin WS (2001) Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: potential significance for tau protein phosphorylation. Neurochem Int 39:341-348.
Sigurdsson EM, Scholtzova H, Mehta PD, Frangione B, Wisniewski T (2001) Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice. Am J Pathol 159:439-447.
Stewart WF, Kawas C, Corrada M, Metter EJ (1997) Risk of Alzheimer's disease and duration of NSAID use. Neurology 48:626-632.
Vodovotz Y, Lucia MS, Flanders KC, Chesler L, Xie QW, Smith TW, Weidner J, Mumford R, Webber R, Nathan C, Roberts AB, Lippa CF, Sporn MB (1996) Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's disease. J Exp Med 184:1425-1433.
Weldon DT, Rogers SD, Ghilardi JR, Finke MP, Cleary JP, O'Hare E, Esler WP, Maggio JE, Mantyh PW (1998) Fibrillar β-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo. J Neurosci 18:2161-2173.
Wilcock GK, Esiri MM, Bowen DM, Hughes AO (1988) The differential involvement of subcortical nuclei in senile dementia of Alzheimer's type. J Neurol Neurosurg Psychiatry 51:842-849.
Willis SA, Nisen PD (1995) Inhibition of lipopolysaccharide-induced IL-1 beta transcription by cyclic adenosine monophosphate in human astrocvtic cells. J Immunol 154:1399-1406.
