Heparin injection into the adult rat hippocampus induces seizures in the absence of macroscopic abnormalities

The pathological hallmarks of Alzheimer's disease include neurofibrillary t angles, neuropil threads and neuritic plaques. Neurofibrillary tangles and neuropil threads are comprised of paired helical filaments which are themse lves composed of a hyperphosphorylated form of the microtubule-associated p rotein tau.(10,13) Neuritic plaques are extracellular deposits of aggregate d beta amyloid associated with neurites containing hyperphosphorylated tau. (3) The mechanisms by which the neurofibrillary tangles and neuritic plaque s develop in Alzhemier's disease are not clear but it is hypothesized that sulphated glycosaminoglycans are important in their formation. This impress ion is based on the finding that the glycosaminoglycan, heparan sulphate, i s found associated with neurofibrillary tangles, neuritic plaques and neuro pil threads(8,16,18) while dermatan sulphate, chondroitin sulphate and kera tan sulphate immunoreactivity is found around neuritic plaques(17) in brain s of Alzheimer's disease patients. Furthermore, in vitro studies demonstrat e that sulphated glycosaminoglycans such as heparan sulphate and the closel y related molecule heparin interact with tau and potentiate its phosphoryla tion by a number of serine/threonine kinases, reduce its ability to bind to microtubules and induce paired helical filament formation, all properties associated with tau isolated from Alzheimer's disease brain.(8,12) Thus, we were interested to learn whether intracerebral injection of the sulphated glycosaminoglycan heparin would give rise to alterations in the cytoskeleta l protein tau in the rat brain. Although no cytoskeletal changes were obser ved, to our considerable surprise we found that the intrahippocampal inject ion of heparin gave rise to seizures. We have investigated this unexpected effect further in vivo and by using in vitro electrophysiological technique s. (C) 1998 IBRO. Published by Elsevier Science Ltd.