The neuron-astrocyte-microglia triad in normal brain aging and a model of neuroinflammation in the rat.

Ageing, characterized by cognitive impairments, is accompanied by up-regulation of proinflammatory responses based on complex alterations between astroglia and neurons. The hippocampus is one of the structures most affected by aging. Here we examined the effect of normal aging and LPS-induced inflammation on astroglia-neuron interaction in the rat hippocampus. GFAP-positive astrocytes density was significantly lower in CA1 Str. radiatum of aged than adult rats (420±16/mm2 vs 522±8/mm2, -20%, P< 0.0001). Confocal microscopy indicated that in aged rats hippocampus astrocytes were smaller, with thicker and shorter branches and with morphological signs of clasmatodendrosis. Astrocyte branches surrounded and infiltrated apoptotic neurons of aged and LPS-treated rats and appeared to help clearing cellular debris which were phagocytated by reactive microglia. Apoptotic cell debris were more numerous in CA1 of aged (496 ±29/mm2) and LPS-treated (106±25/mm2) than in adult rats (22.7±5/mm2, P< 0.001) and were closely apposed to astrocytes cell bodies and branches. Reactive hypertrophic microglia were present in the CA1 Str. Radiatum, often in close association with apoptotic cells. Significant differences were mainly found in the fraction of reactive microglia which was 40% of total in adult, decreased to 33% in aged (P< 0.05) and increased to about 50% of total in LPS-treated rats (P< 0.01). The protein CX3CL1 increased significantly in hippocampus homogenates of aged (+90%) and LPS-treated rats (+84%). A significant decrease of the number of CA1 pyramidal neurons was evident in aged rats in comparison to the two other groups (P< 0.01). These data show that in the hippocampus of aged and LPS-treated rats astrocytes and microglia may help clearing apoptotic cellular debris possibly through CX3CL1 signalling. This might be a protective mechanism to control inflammatory processes and spread of further cellular damage to neighboring tissues.