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The Journal of Neuroscience, March 29, 2006, 26(13):3514-3523; doi:10.1523/JNEUROSCI.5425-05.2006

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Neurobiology of Disease
Improved Long-Term Potentiation and Memory in Young Tau-P301L Transgenic Mice before Onset of Hyperphosphorylation and Tauopathy

Karin Boekhoorn,¹ Dick Terwel,² Barbara Biemans,² Peter Borghgraef,² Olof Wiegert,¹ Ger J. A. Ramakers,³ Koos de Vos,³ Harm Krugers,¹ Takami Tomiyama,⁴ Hiroshi Mori,⁴ Marian Joels,¹ Fred van Leuven,² and Paul J. Lucassen¹

¹Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, 1098 SM Amsterdam, The Netherlands, ²Experimental Genetics Group, Department of Human Genetics, K. U. Leuven, B-3000 Leuven, Belgium, ³Netherlands Institute for Brain Research, 1105 A2 Amsterdam, The Netherlands, and ⁴Department of Neuroscience, Medical School, Abenoku, Osaka 545-8585, Japan

Correspondence should be addressed to Dr. Fred van Leuven, Department of Human Genetics, K. U. Leuven, Campus Gasthuisberg ON1-06.602 06, B-3000 Leuven, Belgium. Email: fredvl{at}med.kuleuven.be

The microtubule binding protein tau is implicated in neurodegenerative tauopathies, including frontotemporal dementia (FTD) with Parkinsonism caused by diverse mutations in the tau gene. Hyperphosphorylation of tau is considered crucial in the age-related formation of neurofibrillary tangles (NFTs) correlating well with neurotoxicity and cognitive defects. Transgenic mice expressing FTD mutant tau-P301L recapitulate the human pathology with progressive neuronal impairment and accumulation of NFT. Here, we studied tau-P301L mice for parameters of learning and memory at a young age, before hyperphosphorylation and tauopathy were apparent. Unexpectedly, in young tau-P301L mice, increased long-term potentiation in the dentate gyrus was observed in parallel with improved cognitive performance in object recognition tests. Neither tau phosphorylation, neurogenesis, nor other morphological parameters that were analyzed could account for these cognitive changes. The data demonstrate that learning and memory processes in the hippocampus of young tau-P301L mice are not impaired and actually improved in the absence of marked phosphorylation of human tau. We conclude that protein tau plays an important beneficial role in normal neuronal processes of hippocampal memory, and conversely, that not tau mutations per se, but the ensuing hyperphosphorylation must be critical for cognitive decline in tauopathies.

Key words: LTP; neurodegeneration; memory; dendate gyrus; neurogenesis; Golgi impregnation

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Received Sept. 27, 2005; revised Feb. 10, 2006; accepted Feb. 13, 2006.

Correspondence should be addressed to Dr. Fred van Leuven, Department of Human Genetics, K. U. Leuven, Campus Gasthuisberg ON1-06.602 06, B-3000 Leuven, Belgium. Email: fredvl{at}med.kuleuven.be

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