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The Journal of Neuroscience, November 16, 2005, 25(46):10637-10647; doi:10.1523/JNEUROSCI.3279-05.2005

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Neurobiology of Disease
Age-Dependent Neurofibrillary Tangle Formation, Neuron Loss, and Memory Impairment in a Mouse Model of Human Tauopathy (P301L)

Martin Ramsden,¹ Linda Kotilinek,¹ Colleen Forster,² Jennifer Paulson,¹ Eileen McGowan,⁶ Karen SantaCruz,² Aaron Guimaraes,¹ Mei Yue,⁶ Jada Lewis,⁶ George Carlson,⁷ Michael Hutton,⁶ and Karen H. Ashe^1,3,4,5

Departments of ¹Neurology, ²Laboratory Medicine and Pathology, and ³Neuroscience and ⁴Graduate Program in Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota 55455, ⁵Geriatric Research, Education, and Clinical Center, Minneapolis Veterans Affairs Hospital, Minneapolis, Minnesota 55417, ⁶Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida 32224, and ⁷McLaughlin Research Institute, Great Falls, Montana 59404

Here, we describe the generation of a novel transgenic mouse model of human tauopathy. The rTg(tau_P301L)4510 mouse expresses the P301L mutation in tau (4R0N) associated with frontotemporal dementia and parkinsonism linked to chromosome 17. Transgene expression was driven by a forebrain-specific Ca²⁺ calmodulin kinase II promoter system resulting in high levels of expression in the hippocampus and neocortex. Importantly, transgene expression in this model is induced via the tetracycline-operon responsive element and is suppressed after treatment with doxycycline. Continued transgene expression in rTg(tau_P301L)4510 mice results in age-dependent development of many salient characteristics of hereditary human dementia. From an early age, immunohistochemical studies demonstrated abnormal biochemical processing of tau and the presence of pathological conformation- and phosphorylation-dependent epitopes. Neurofibrillary tangle (NFT) pathology was first observed in the neocortex and progressed into the hippocampus and limbic structures with increasing age. Consistent with the formation of NFTs, immunoblots indicated an age-dependent transition of accumulating tau species from Sarkosyl soluble 55 kDa to insoluble hyperphosphorylated 64 kDa. Ultrastructural analysis revealed the presence of straight tau filaments. Furthermore, the effects of tau_P301L expression on spatial reference memory were longitudinally tested using the Morris water maze. Compared with nontransgenic age-matched control littermates, rTg(tau_P301L)4510 mice developed significant cognitive impairments from 4 months of age. Memory deficits were accompanied by gross forebrain atrophy and a prominent loss of neurons, most strikingly in hippocampal subdivision CA1. Collectively, these data describe a novel transgenic mouse that closely mimics human tauopathy and may represent an important model for the future study of tau-related neurodegenerative disease.

Key words: tau; transgenic; neurodegeneration; hippocampus; Alzheimer; FTDP-17

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Received Aug 4, 2005; revised September 22, 2005; accepted September 27, 2005.

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