Effects of tumor necrosis factor-alpha central administration on hippocampal damage in rat induced by amyloid beta-peptide (25-35).
Male Wistar rats received unilateral intrahippocampal injections of 3 nmol (3.18 microg) aggregated Abeta(25-35), intracerebroventricular bilateral injections of 0.5 microg human recombinant TNFalpha or both (Abeta(25-35) + TNFalpha-treated animals). Seven days after the surgery brain sections were stained with cresyl violet (Nissl), for fragmented DNA (TUNEL), glial fibrillar acidic protein (GFAP) and isolectin B4-reactive microglia. In addition, caspase-3 activity in brain regions was measured fluorometrically. The morphology of the hippocampus after the injection of Abeta(25-35) or both Abeta(25-35) and TNFalpha (but not TNFalpha alone) showed cell loss in the CA1 pyramidal cell layer. The extension of neuronal degeneration measured in the CA1 field was significantly larger in Abeta(25-35)-treated groups compared to the contralateral hemisphere of both vehicle-treated controls and animals injected with TNFalpha alone. TNFalpha augmented the Abeta(25-35)-induced damage, significantly increasing the extension of degenerating area. Administration of Abeta(25-35) caused reactive gliosis in the ipsilateral hemisphere as demonstrated by upregulation of GFAP expression and the presence of hypertrophic astrocytes in the hippocampus. This effect was much more prominent in the hippocampi of rats treated with Abeta(25-35) + TNFalpha but absent after administration of TNFalpha alone. In both Abeta(25-35)-treated groups, the damaged area of the hippocampal CA1 field and lateral band of dentate gyrus displayed many darkly stained round isolectin B4-positive phagocyte-like microglial cells. Sparse TUNEL-positive nuclei were found in the hippocampi of rats treated with Abeta(25-35) alone or together with TNFalpha, but not in the control brain sections or in brain sections of TNFalpha-injected animals. The activity of caspase-3 increased significantly in the ipsilateral hippocampus after the injection of Abeta(25-35). Surprisingly, administration of TNFalpha into the cerebral ventricles prevented this Abeta(25-35)-induced increase in hippocampal caspase-3 activity. The results are discussed from the perspective of dual (neuroprotective and neurodestructive) roles of TNF in the brain.
Stepanichev
Mikhail Yu
MY
Department of Functional Biochemistry of the Nervous System, Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, Russia.
Zdobnova
Irina M
IM
Yakovlev
Alexander A
AA
Onufriev
Mikhail V
MV
Lazareva
Natalia A
NA
Zarubenko
Irina I
II
Gulyaeva
Natalia V
NV
D016229:Amyloid beta-Peptides / Q000502:physiology* / Q000633:toxicity; D000818:Animals; D001253:Astrocytes; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004347:Drug Interactions; D007839:Functional Laterality; D005904:Glial Fibrillary Acidic Protein / Q000187:drug effects / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced / Q000517:prevention & control*; D006624:Hippocampus / Q000293:injuries* / Q000473:pathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007276:Injections, Intraventricular; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D008297:Male; D017628:Microglia / Q000378:metabolism; D009410:Nerve Degeneration; D010446:Peptide Fragments / Q000502:physiology* / Q000633:toxicity; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D005904:Glial Fibrillary Acidic Protein; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C113041:amyloid beta-protein (35-25)