Hirano bodies are actin rich, rod-shaped, cytoplasmic, paracrystalline inclusions found predominantly in the central nervous system in association with a variety of conditions including aging and Alzheimers disease. Since most studies of Hirano bodies have been performed in post-mortem samples from patients, the physiological role of Hirano bodies has not been investigated. We have developed a cell culture model system for the formation of Hirano bodies in H4 neuroglioma cells using a modified form of a 34 kDa actin bundling protein from Dictyostelium named CT-GFP. Using this cell culture system, association of a C-terminal fragment of amyloid- precursor protein (AICD) and adapter protein Fe65 with model Hirano bodies were investigated. Further, cells with Hirano bodies down-regulate both AICD-dependent caspase activation and cell death. Finally, cells with Hirano bodies show significantly reduced levels of AICD- and Fe65-dependent transcriptional activity. Therefore, association of AICD with Hirano bodies may impede its function in promoting apoptosis and modulating transcription. These results suggest that Hirano bodies may function as adaptive structures in Alzheimers disease by limiting AICD-dependent neurotoxicity. We generated a mouse model of Hirano bodies to examine the physiological effects and roles of Hirano bodies in the brain. We used Thy1 promoter to drive tissue specific expression of Cre recombinase to induce expression of the CT-GFP transgene that promotes formation of Hirano bodies in cell cultures. The expression of CT-GFP was detected and largely co-localized with F-actin in hippocampus beginning at P0. The mouse model of Hirano bodies showed paracrystalline F-actin and eosinophilic rod-like structure. These inclusions were first detected in +/++the hippocampus in 6 month R26CT;Cre mice. The number, density, and morphology of neurons in the hippocampus appeared normal. Studies of long term potentiation in hippocampal slice cultures revealed only minor (not significant) differences in synaptic plasticity between Hirano body and littermate control mice, consistent with the interpretation that Hirano bodies are not toxic or deleterious to neuronal function. These mice will be extremely valuable tools for future studies of the physiological function of Hirano bodies in vivo in normal mice, during aging, and in mouse models of diseases including Alzheimers disease.
