Memory deficits correlate with tau and spine pathology in P301S MAPT transgenic mice H. Xu*†, T. W. Rösler†, T. Carlsson‡§, A. de Andrade†§, J. Bruch*†, M. Höllerhage*, W. H. Oertel§ and G. U. Höglinger*†§ *Department of Neurology, Technical University Munich, †Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, §Department of Neurology, Philipps-University, Marburg, Germany, and ‡Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden H. Xu, T. W. Rösler, T. Carlsson, A. de Andrade, J. Bruch, M. Höllerhage, W. H. Oertel and G. U. Höglinger (2014) Neuropathology and Applied Neurobiology 40, 833–843 Memory deficits correlate with tau and spine pathology in P301S MAPT transgenic mice Aim: P301S MAPT transgenic mice (P301S mice) are a widely used model of frontotemporal dementia and parkin- sonism linked to chromosome 17 with tau pathology (FTDP-17-tau). However, a systematic correlation between cognitive deficits and cellular tau pathology at different ages is still missing. Therefore, our study investigated memory deficits of P301S mice in relation to pathological tau species and dendritic spine pathology throughout adulthood. Methods: We analysed P301S mice behaviour- ally with the novel open field, rotarod, and Morris water maze tests to measure deficits in locomotion, balance and cognition, respectively; immunohistochemically with dif- ferent tau antibodies for specific tau species; and with Golgi staining for dendritic spine pathology. Results: We con- firmed the occurrence of locomotor deficits at an age of 5 months and newly report memory deficits from 2.5 months of age onwards. At this early age, MC1 and CP13, but not AT180 immunoreactivity, was prominent in the hippocampus of P301S mice. Neuronal cell loss in the hippocampus of P301S mice was not observed to occur till 6months of age. However, there was a significant reduc- tion in the density of dendritic spines from young adult- hood onwards in hippocampal pyramidal neurones. Conclusion: In P301S mice, memory deficits precede the onset of locomotor dysfunction and coincide with the appearance of conformationally changed, S202- phosphorylated tau and reduced spine density in the absence of neuronal cell loss in the hippocampus. Our finding provides insights into the toxic effects of different tau species in vivo and may facilitate the development of new therapies against neurodegenerative tauopathies. Keywords: dendritic spine, FTDP-17-tau, memory deficit, P301S transgenic mouse, tau, tauopathy Introduction The microtubule-associated protein tau is abundantly expressed in the central nervous system and has been linked to the pathology of several neurodegenerative dis- eases, jointly termed tauopathies. Tau was found to par- ticipate in stabilizing and assembling microtubules [1], however, until today the full physiological function of tau remains unknown. In adult neuronal cells, mainly six isoforms of tau exist in a homeostatic balance [2]. Muta- tions of the tau encoding gene (MAPT), altered isoform expression, hyperphosphorylation or conformational changes of the tau protein can disturb the physiological balance, leading to tau pathologies [3]. Tauopathies can show diverse clinical phenotypes ranging from dementia Correspondence: Günter U. Höglinger, Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Max-Lebsche-Platz 30, 81377 Munich, Germany. Tel: +49 89 44007 8406; Fax: +49 89 44007 8420; E-mail: guenter.hoeglinger@dzne.de 833 © 2014 British Neuropathological Society Neuropathology and Applied Neurobiology (2014), 40, 833–843 doi: 10.1111/nan.12160