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 μg) aggregated Aβ(25–35), intracerebroventricular bilateral injections of 0.5 μg human recombinant TNFα or both (Aβ(25–35) + TNFα‐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 Aβ(25–35) or both Aβ(25–35) and TNFα (but not TNFα alone) showed cell loss in the CA1 pyramidal cell layer. The extension of neuronal degeneration measured in the CA1 field was significantly larger in Aβ(25–35)‐treated groups compared to the contralateral hemisphere of both vehicle‐treated controls and animals injected with TNFα alone. TNFα augmented the Aβ(25–35)‐induced damage, significantly increasing the extension of degenerating area. Administration of Aβ(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 Aβ(25–35) + TNFα but absent after administration of TNFα alone. In both Aβ(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 Aβ(25–35) alone or together with TNFα, but not in the control brain sections or in brain sections of TNFα‐injected animals. The activity of caspase‐3 increased significantly in the ipsilateral hippocampus after the injection of Aβ(25–35). Surprisingly, administration of TNFα into the cerebral ventricles prevented this Aβ(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. © 2002 Wiley‐Liss, Inc.