Characterization of Pathology in Transgenic Mice Over-Expressing Human Genomic and cDNA Tau Transgenes K. Duff, H. Knight,* L. M. Refolo, S. Sanders, ² X. Yu, ² M. Picciano, B. Malester, M. Hutton, ² J. Adamson, ² M. Goedert, ‡ K. Burki, § and P. Davies  Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York 10962; *Commonwealth Biotechnologies, Inc., Richmond, Virginia 23235; † Mayo Clinic, Jacksonville, Florida 32224; § Novartis Pharmaceuticals AG, Basel CH-4002, Switzerland; ‡ MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom; and  Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461 Received September 21, 1999; revised November 19, 1999; accepted December 9, 1999 To examine the normal cellular function of tau and its role in pathogenesis, we have created transgenic mice that overexpress a tau transgene derived from a human PAC that contains the coding sequence, intronic regions, and regulatory regions of the human gene. All six isoforms of human tau are represented in the transgenic mouse brain at the mRNA and protein level and the human tau is distributed in neurites and at synapses, but is absent from cell bodies. A comparison between the genomic tau mice and mice that overexpress a tau cDNA transgene shows that overall, the distribution of tau is similar in the two lines, but human tau is located in the somatodendritic compartment of many neurons in the cDNA mice. Tau-immunoreactive axonal swellings were found in the spinal cords of the cDNA mice, which correlated with a hind-limb abnormality, whereas neuropathology was essentially normal in the genomic mice up to 8 months of age.  2000 Academic Press INTRODUCTION The human tau protein has been implicated in the pathogenesis of several human neurodegenerative dis- eases including Alzheimer’s disease (AD) and frontal temporal lobe dementia (Hardy et al., 1998; Spillantini and Godert, 1998). The pathology of AD is defined as the presence of amyloid-containing plaques and neuro- fibrillary tangles (NFTs) composed of tau arranged into paired helical filaments (PHFs). Mutations in the tau gene lead to a range of tauopathies (termed Fronto-Temporal Dementia and Parkinsonism linked to chromosome 17; FTDP-17), where tau takes the form of PHF (Spillantini et al., 1996; Poorkaj et al., 1998; Hutton et al., 1998) or twisted ribbons (Spillantini et al., 1997, 1998; Hutton et al., 1998; Reed et al., 1998). Although the mechanisms underlying the develop- ment of tauopathy in these diseases are unknown, hyperphosphorylation of tau has been linked to AD (Iqbal and Iqbal, 1996), and disruption of microtubule binding and assembly has been linked to FTDP-17 missense mutations (Hasegawa et al., 1998; Hong et al., 1998). Human tau is alternatively spliced to generate six isoforms that differ in the presence or absence of exons 2,3, or 10 (Godert et al., 1989; Andreadis et al., 1992). Splicing out of exon 10 generates a tau protein with 3 microtubule binding domain repeats (3R), whereas its inclusion generates tau with 4 repeats (4R). The normal human brain maintains an approximately equal ratio of 4R to 3R tau but this ratio is shifted in favor of more 4R tau in FTDP-17 patients with splice site mutations (Godert and Jakes, 1990; Spillantini et al., 1998; Hong et al., 1998; Godert et al., 1999; Grover et al., 1999). Biochemical evidence suggests that microtubule bind- ing and assembly is disrupted by some missense mutations in tau (Hasagawa et al., 1998; Hong et al., 1998; Dayanandan et al., 1999); however, the mecha- Neurobiology of Disease 7, 87–98 (2000) doi:10.1006/nbdi.1999.0279, available online at http://www.idealibrary.com on 87 0969-9961/00 $35.00 Copyright  2000 by Academic Press All rights of reproduction in any form reserved.