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Experimental Genetics Group

Bolleke Abstract   Pijltje
Improved long-term potentiation and memory in young tau-P301L transgenic mice before onset of hyperphosphorylation and tauopathy.

J Neurosci. 2006 Mar 29;26(13):3514-23.

Boekhoorn K1, Terwel D2, Biemans B2, Borghgraef P2, Wiegert O1, Ramakers GJ3, de Vos K3, Krugers H1, Tomiyama T4, Mori H4, Joels M1, van Leuven F2, Lucassen PJ1.

1Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
2Experimental Genetics Group, Department of Human Genetics, K.U. Leuven, Leuven, Belgium.
3Netherlands Institute for Brain Research, Amsterdam, The Netherlands.
4Department of Neuroscience, Medical School, Osaka, Japan.

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.

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