The potential contribution of ApoE to AD pathology was cast in a novel light in data presented as a poster today by Huang et al. They were studying the fate of ApoE when expressed by transient transfection in Neuro-2a cells. The ApoE was tagged with green fluorescent protein (GFP) to allow for visualization of its intracellular fate. Previous studies from this group had shown that full-length ApoE exhibits isoform-dependent differences in the cellular distribution of the protein. In the present study, ApoE was truncated at its carboxy terminal end (residues 272-299) to see if this would affect its intracellular fate. Surprisingly, the truncated ApoE was found to produced tangle-like structures in the cells, with the ApoE4 isoform being much more effective than the apoE3 isoform. The tangle-like intracellular structures stained with an anti-tau antibody (RT97) as well as with antibodies to neurofilament heavy chain. They appeared to be composed of dense bundles of filaments at the electron microscopic level. This aberrant intracellular formation apparently was toxic, because the cells eventually died (MTT assay). Similar isoform-specific effects were obtained if the truncated GFP-ApoE was added exogenously. Although the mechanism is unknown, the demonstration of isoform-specific effects of ApoE on cytoskeletal structures is consistent with a possible role for this protein in tangle formation in AD. Huang says that transgenic mice have been developed using similar constructs and are awaiting analysis.—Keith Crutcher

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