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Published online 13 November 2006. doi:10.1083/jcb.200605187
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 4, 541-546
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Tau-dependent microtubule disassembly initiated by prefibrillar ß-amyloid



Michelle E. King1, Ho-Man Kan1, Peter W. Baas4, Alev Erisir2, Charles G. Glabe5, and George S. Bloom1,3

1 Department of Biology, 2 Department of Psychology, and 3 Department of Cell Biology, University of Virginia, Charlottesville, VA 22904
4 Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129
5 Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, CA 92697

Correspondence to Michelle E. King: mk2j{at}virginia.edu; or George S. Bloom: gsb4g{at}virginia.edu

Alzheimer's Disease (AD) is defined histopathologically by extracellular ß-amyloid (Aß) fibrils plus intraneuronal tau filaments. Studies of transgenic mice and cultured cells indicate that AD is caused by a pathological cascade in which Aß lies upstream of tau, but the steps that connect Aß to tau have remained undefined. We demonstrate that tau confers acute hypersensitivity of microtubules to prefibrillar, extracellular Aß in nonneuronal cells that express transfected tau and in cultured neurons that express endogenous tau. Prefibrillar Aß42 was active at submicromolar concentrations, several-fold below those required for equivalent effects of prefibrillar Aß40, and microtubules were insensitive to fibrillar Aß. The active region of tau was localized to an N-terminal domain that does not bind microtubules and is not part of the region of tau that assembles into filaments. These results suggest that a seminal cell biological event in AD pathogenesis is acute, tau-dependent loss of microtubule integrity caused by exposure of neurons to readily diffusible Aß.

Abbreviations used in this paper: Aß, ß-amyloid; AD, Alzheimer's disease.


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