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American Journal of Pathology, Vol 151, 265-271, Copyright © 1997 by American Society for Investigative Pathology

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Carboxyl-terminal fragments of beta-amyloid precursor protein bind to microtubules and the associated protein tau

K Islam and E Levy
Department of Pharmacology, New York University Medical Center 10016, USA.

Alzheimer's disease is a neurodegenerative disorder characterized by protein depositions in intracellular and extracellular spaces in the brain. The intraneuronal deposits are formed by neurofibrillary tangles composed mainly of abnormally phosphorylated tau, a microtubule- associated protein, whereas the major constituent of the amyloid deposited extracellularly in the brain parenchyma and vessel walls is amyloid beta-protein (A beta). The proteolytic processing of the beta- amyloid precursor protein (beta PP) results in the generation of a complex set of carboxyl-terminal peptides that contain A beta. In this study, we have used fusion proteins containing carboxyl-terminal fragments of beta PP to investigate the association of beta PP with cellular components. We demonstrate that specific domains within the carboxyl end of beta PP contain binding sites for cytoskeletal components; one, within residues 1 to 28 of A beta, binds directly to tubulin, and the second one, within sequences carboxyl-terminal to A beta, binds tau and tubulin. We propose that the two neuropathological hallmarks of Alzheimer's disease, A beta deposition and neurofibrillary tangles, represent the residual of a disrupted beta PP-tubulin-tau complex.

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