Intraneuronal Filamentous Deposits in Alzheimer's Disease and Other Dementing Disorders

M. Goedert

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MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, UK

Abundant neuritic plaques and neurofibrillary lesions in certain brain regions constitute the defining neuropathological characteristics of Alzheimer's disease. The paired helical filament (PHF) is the major fibrous component of the neurofibrillary lesions. It consists predominantly of microtubule-associated protein tau. Similar filamentous tau lesions are found in other primary dementing disorders, such as Pick's disease and familial frontotemporal dementias with Parkinsonism that have been linked genetically to the same region of the long arm of chromosome 17 that the tau gene maps to. PHF-tau contains all six tau isoforms, but in a hyperphosphorylated state. Hyperphosphorylation of tau is anearly event in the development of the neurofibrillary pathology which leads to its inability to bind to microtubules. However, the role of hyperphosphorylation of tau in filament assembly is less clear. We have shown that sulphated glycosaminoglycans induce bulk assembly of recombinant tau into Alzheimer-like filaments under physiological conditions, in a phosphorylation-independent manner. The ability of glycosaminoglycans to induce tau filament assembly is dependent of the degree of glycosaminoglycan sulphation. The interaction between tau and sulphated glycosaminoglycans prevents the binding of tau to microtubules and results in rapid microtubule disassembly. Sulphated glycosaminoglycans also markedly stimulate phosphorylation of tau by a number of protein kinases. Moreover, heparan sulphate is present in nerve cells in the Alzheimer's disease brain at the early stages of neurofibrillary pathology. Taken together, these findings suggest that an interaction between tau and sulphated glycosaminoglycans may constitute a central event in the development of the intraneuronal filamentous pathology of Alzheimer's disease and other tauopathies. Lewy bodies, the defining neuropathological characteristic of Parkinson's disease and dementia with Lewy bodies, constitute the second most common filamentous intraneuronal pathology, after the neurofibrillary pathology of Alzheimer's disease. Recent work on the presence of a-synuclein in Lewy body filaments will be presented.