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J Neurosci. 2019 Jun 24. pii: 2845-18. doi: 10.1523/JNEUROSCI.2845-18.2019. [Epub ahead of print]

Ectopic expression induces abnormal somatodendritic distribution of tau in the mouse brain.

Author information

1
Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe-shi, Kyoto 610-0394, Japan.
2
Laboratory of Ion Channel Pathophysiology, Graduate School of Brain Science, Doshisha University, Kyotanabe-shi, Kyoto 610-0394, Japan.
3
Division of Molecular Genetics, Shigei Medical Research Institute, Minami-Ku, Okayama 701-0202, Japan.
4
Department of Alzheimer's Disease, Faculty of Life Science, Gakushuin University, Toshima-ku, Tokyo 171-0031, Japan.
5
Center for Research in Neurodegenerative Diseases, Doshisha University, Kyotanabe-shi, Kyoto 610-0394, Japan.
6
Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
7
Central Institute for Experimental Animals (CIEA), Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan.
8
Department of Neuroscience, Graduate School of Medicine, Osaka City University, Abeno-Ku, Osaka 545-8585, Japan.
9
Neuropathology, The Brain Bank for Aging Research, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
10
Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe-shi, Kyoto 610-0394, Japan tomiyasa@mail.doshisha.ac.jp.

Abstract

Tau is a microtubule-associated protein that is localized to the axon. In Alzheimer's disease, the distribution of tau undergoes a remarkable alteration, leading to the formation of tau inclusions in the somatodendritic compartment. To investigate how this mis-localization occurs, we recently developed immunohistochemical tools that can separately detect endogenous mouse and exogenous human tau with high sensitivity, which allows us to visualize not only the pathological but pre-aggregated tau in mouse brain tissues of both sex. Using these antibodies, we found that in tau transgenic mouse brains exogenous human tau was abundant in dendrites and somata even in the presymptomatic period, whereas the axonal localization of endogenous mouse tau was unaffected. In stark contrast, exogenous tau was properly localized to the axon in human tau knock-in mice. We tracked this difference to the temporal expression patterns of tau. Endogenous mouse tau and exogenous human tau in human tau knock-in mice exhibited high expression levels during the neonatal period and strong suppression into the adulthood. However, human tau in transgenic mice was expressed continuously and at high levels in adult animals. These results indicated the uncontrolled expression of exogenous tau beyond the developmental period as a cause of mis-localization in the transgenic mice. Super-resolution microscopic and biochemical analyses also indicated that the interaction between microtubules and exogenous tau was impaired only in the tau transgenic mice, but not in knock-in mice. Thus, the ectopic expression of tau may be critical for its somatodendritic mis-localization, a key step of the tauopathy.SIGNIFICANCE STATEMENTSomatodendritic localization of tau may be an early step leading to the neuronal degeneration in tauopathies. However, the mechanisms of the normal axonal distribution of tau and the mis-localization of pathological tau remain obscure. Our immunohistochemical and biochemical analyses demonstrated that the endogenous mouse tau is transiently expressed in neonatal brains, that exogenous human tau expressed corresponding to such tau expression profile can distribute into the axon, and that the constitutive expression of tau into adulthood (ex. human tau in Tg mice) results in abnormal somatodendritic localization. Thus, the expression profile of tau is tightly associated with the localization of tau, and the ectopic expression of tau in matured neurons may be involved in the pathogenesis of tauopathy.

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