Effects of intrahippocampal colchicine administration on the levels and localization of microtubule-associated proteins, tau and MAP2.

Colchicine, a microtubule disrupting agent, has been used to model several aspects of Alzheimer's disease-related neuropathology. The formation of neurofibrillary tangles, one of the pathological hallmarks of Alzheimer's disease, involves the loss of tau (a low mol. wt. microtubule-associated protein) from axons and accumulation of abnormally phosphorylated tau in somatodendritic compartments. Other cytoskeletal proteins, such as microtubule-associated protein 2 (MAP2), disappear as tau accumulates. The present study was directed at evaluating the effects of colchicine on tau and MAP2, to determine if changes in their levels or distribution might be similar to those which precede the formation of neurofibrillary tangles in Alzheimer's disease. Six hours following intrahippocampal colchicine injection (3.5 micrograms injected into two rostro-caudal locations) tau-1 immunostaining was enhanced in CA1 s. radiatum and decreased in the outer molecular layer of the dentate gyrus. In addition, a shift in the relative abundance of tau isoforms was observed in Western blots. Both the immunocytochemical and immunoblot results are consistent with a dephosphorylation of tau. Loss of MAP2 was evident 3 days postinjection which coincided with a loss of Cresyl violet staining in granule cell, CA3, subicular and entorhinal neurons. Accumulation of tau or MAP2 in neuronal perikarya was not observed at any postinjection time points. Thus, intrahippocampal colchicine administration does not model the shift in tau localization, excessive tau phosphorylation, or other cytoskeletal alterations that are suggested to precede or accompany the formation of neurofibrillary pathology in Alzheimer's disease.