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The Journal of Neuroscience, April 4, 2007, 27(14):3650-3662; doi:10.1523/JNEUROSCI.0587-07.2007

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Neurobiology of Disease
Accumulation of Pathological Tau Species and Memory Loss in a Conditional Model of Tauopathy

Zdenek Berger,¹ Hanno Roder,¹ Amanda Hanna,¹ Aaron Carlson,¹ Vijayaraghavan Rangachari,¹ Mei Yue,¹ Zbigniew Wszolek,¹ Karen Ashe,² Joshua Knight,¹ Dennis Dickson,¹ Cathy Andorfer,¹ Terrone L. Rosenberry,¹ Jada Lewis,¹ Mike Hutton,¹ and Christopher Janus¹

¹Mayo Clinic Jacksonville, Jacksonville, Florida 32224, and ²Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

Correspondence should be addressed to Mike Hutton, Mayo Clinic Jacksonville, 4500 San Pablo Road, Birdsall Building, Jacksonville, FL 32224. Email: hutton.michael{at}mayo.edu

Neurofibrillary tangles (NFTs) are a pathological hallmark of Alzheimer's disease and other tauopathies, but recent studies in a conditional mouse model of tauopathy (rTg4510) have suggested that NFT formation can be dissociated from memory loss and neurodegeneration. This suggests that NFTs are not the major neurotoxic tau species, at least during the early stages of pathogenesis. To identify other neurotoxic tau protein species, we performed biochemical analyses on brain tissues from the rTg4510 mouse model and then correlated the levels of these tau proteins with memory loss. We describe the identification and characterization of two forms of tau multimers (140 and 170 kDa), whose molecular weight suggests an oligomeric aggregate, that accumulate early in the pathogenic cascade in this mouse model. Similar tau multimers were detected in a second mouse model of tauopathy (JNPL3) and in tissue from patients with Alzheimer's disease and FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17). Moreover, levels of the tau multimers correlated consistently with memory loss at various ages in the rTg4510 mouse model. Our findings suggest that accumulation of early-stage aggregated tau species, before the formation of NFT, is associated with the development of functional deficits during the pathogenic progression of tauopathy.

Key words: tau; transgenic; neurodegeneration; Alzheimer's disease; FTDP-17; toxicity

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Received Sept. 9, 2006; accepted Feb. 22, 2007.

Correspondence should be addressed to Mike Hutton, Mayo Clinic Jacksonville, 4500 San Pablo Road, Birdsall Building, Jacksonville, FL 32224. Email: hutton.michael{at}mayo.edu

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