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The Journal of Neuroscience, June 1, 2005, 25(22):5446-5454; doi:10.1523/JNEUROSCI.4637-04.2005

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Neurobiology of Disease
Cell-Cycle Reentry and Cell Death in Transgenic Mice Expressing Nonmutant Human Tau Isoforms

Cathy Andorfer,¹ Christopher M. Acker,² Yvonne Kress,² Patrick R. Hof,³ Karen Duff,⁴ and Peter Davies^1,2

Departments of ¹Neuroscience and ²Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, ³Kastor Neurobiology of Aging Laboratories and Fishberg Research Center for Neurobiology, Department of Geriatrics and Adult Development, and Department of Ophthalmology, Mount Sinai School of Medicine, New York, New York 10029, and ⁴Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York 10962

Mutations in the microtubule-associated protein tau gene have been linked to neurofibrillary tangle (NFT) formation in several neurodegenerative diseases known as tauopathies; however, no tau mutations occur in Alzheimer's disease, although this disease is also characterized by NFT formation and cell death. Importantly, the mechanism of tau-mediated neuronal death remains elusive. Aged mice expressing nonmutant human tau in the absence of mouse tau (htau mice) developed NFTs and extensive cell death. The mechanism of neuron death was investigated in htau mice, and surprisingly, the presence of tau filaments did not correlate directly with death within individual cells, suggesting that cell death can occur independently of NFT formation. Our observations show that the mechanism of neurodegeneration involved reexpression of cell-cycle proteins and DNA synthesis, indicating that nonmutant tau pathology and neurodegeneration may be linked via abnormal, incomplete cell-cycle reentry.

Key words: cell cycle; neurofibrillary tangle; cell death; transgenic; nonmutant tau; neurodegeneration

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Received Nov 11, 2004; revised April 14, 2005; accepted April 26, 2005.

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