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The possible link between amnesia induced by central administration of beta-amyloid (25-35) (Abeta(25-35)) and neurodegenerative changes in the hippocampus was studied. Male Wistar rats received single intracerebroventricular injections of Abeta(25-35) at a dose of 15 nmoles and one month later were trained in an eight-arm radial maze. Training was followed by histological assessment of the state of the hippocampus on brain sections stained with hematoxylin and eosin. Abeta(25-35) induced impairments in long-term (reference) and working memory on testing in the maze. There was a moderate reduction in the number of neurons in hippocampal field CA1; there was no change in the number of cells in field CA3. The numbers of errors made by the animals on testing in the maze were found to correlate negatively with the numbers of nerve cells in hippocampal field CA1. Thus, this is the first demonstration that impairments of learning and memory induced by single doses of Abeta(25-35) are specifically associated with neurodegenerative changes in hippocampal field CA1 in rats.

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.

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