Desacyl-ghrelin and synthetic GH-secretagogues modulate the production of inflammatory cytokines in mouse microglia cells stimulated by beta-amyloid fibrils.
Data from Alzheimer's disease (AD) patients and AD animal models demonstrate the accumulation of inflammatory microglia at sites of insoluble fibrillar beta-amyloid protein (fAbeta) deposition. It is known that fAbeta binds to CD36, a type B scavenger receptor also involved in internalization of oxidized low-density lipoprotein (LDL), and initiate a signaling cascade that regulates microglial recruitment, activation, and secretion of inflammatory mediators leading to neuronal dysfunction and death. The recent demonstration of a binding site for the growth hormone secretagogues (GHS) on CD36 prompted us to ascertain whether ghrelin and synthetic GHS could modulate the synthesis of inflammatory cytokines in fAbeta-activated microglia cells. We demonstrate that N9 microglia cells express the CD36 and are a suitable model to study the activation of inflammatory cytokines synthesis. In fact, in N9 cells exposed to fAbeta(25-35) for 24 hr, the expression of interleukin (IL)-1beta and IL-6 mRNA significantly increased. Interestingly, 10(-7) M desacyl-ghrelin, hexarelin, and EP80317 in the nanomolar range effectively counteracted fAbeta(25-35) stimulation of IL-6 mRNA levels, whereas ghrelin was ineffective. Similarly, the effects of fAbeta(25-35) on IL-1beta mRNA levels were attenuated by desacyl-ghrelin, hexarelin, and EP80317, but not ghrelin. Because we have observed that the specific GHS receptor GHS-R1a is not expressed in N9 cells, the actions of GHS should be mediated by different receptors. Reportedly, hexarelin and EP80317 are capable of binding the CD36 in mouse macrophages and reducing atherosclerotic plaque deposition in mice. We conclude that desacyl-ghrelin, hexarelin, and EP80317 might interfere with fAbeta activation of CD36 in microglia cells.
Bulgarelli
Ilaria
I
Department of Experimental Medicine, University of Milano-Bicocca, Milan, Italy.
Tamiazzo
Laura
L
Bresciani
Elena
E
Rapetti
Daniela
D
Caporali
Simona
S
Lattuada
Donatella
D
Locatelli
Vittorio
V
Torsello
Antonio
A
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D018955:CD36 Antigens / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D004660:Encephalitis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D054439:Ghrelin / Q000494:pharmacology*; D005911:Gliosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D013006:Growth Hormone / Q000819:agonists* / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D002537:Intracranial Arteriosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000633:toxicity; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism
D016229:Amyloid beta-Peptides; D018955:CD36 Antigens; D016207:Cytokines; C468852:EP80317; D054439:Ghrelin; D053583:Interleukin-1beta; D015850:Interleukin-6; D008077:Lipoproteins, LDL; D009842:Oligopeptides; D010446:Peptide Fragments; D012333:RNA, Messenger; C074636:amyloid beta-protein (25-35); C422650:ghrelin, des-n-octanoyl; C086184:hexarelin; D013006:Growth Hormone