Hippocampal tau oligomerization early in tau pathology coincides with a transient alteration of mitochondrial homeostasis and DNA repair in a mouse model of tauopathy

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Hippocampal tau oligomerization early in tau pathology coincides with a transient alteration of mitochondrial homeostasis and DNA repair in a mouse model of tauopathy. / Zheng, Jin; Akbari, Mansour; Schirmer, Claire; Reynaert, Marie Line; Loyens, Anne; Lefebvre, Bruno; Buée, Luc; Croteau, Deborah L.; Galas, Marie Christine; Bohr, Vilhelm A.

In: Acta Neuropathologica Communications, Vol. 8, No. 1, 25, 2020.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Zheng, J, Akbari, M, Schirmer, C, Reynaert, ML, Loyens, A, Lefebvre, B, Buée, L, Croteau, DL, Galas, MC & Bohr, VA 2020, 'Hippocampal tau oligomerization early in tau pathology coincides with a transient alteration of mitochondrial homeostasis and DNA repair in a mouse model of tauopathy', Acta Neuropathologica Communications, vol. 8, no. 1, 25. https://doi.org/10.1186/s40478-020-00896-8

APA

Zheng, J., Akbari, M., Schirmer, C., Reynaert, M. L., Loyens, A., Lefebvre, B., ... Bohr, V. A. (2020). Hippocampal tau oligomerization early in tau pathology coincides with a transient alteration of mitochondrial homeostasis and DNA repair in a mouse model of tauopathy. Acta Neuropathologica Communications, 8(1), [25]. https://doi.org/10.1186/s40478-020-00896-8

Vancouver

Zheng J, Akbari M, Schirmer C, Reynaert ML, Loyens A, Lefebvre B et al. Hippocampal tau oligomerization early in tau pathology coincides with a transient alteration of mitochondrial homeostasis and DNA repair in a mouse model of tauopathy. Acta Neuropathologica Communications. 2020;8(1). 25. https://doi.org/10.1186/s40478-020-00896-8

Author

Zheng, Jin ; Akbari, Mansour ; Schirmer, Claire ; Reynaert, Marie Line ; Loyens, Anne ; Lefebvre, Bruno ; Buée, Luc ; Croteau, Deborah L. ; Galas, Marie Christine ; Bohr, Vilhelm A. / Hippocampal tau oligomerization early in tau pathology coincides with a transient alteration of mitochondrial homeostasis and DNA repair in a mouse model of tauopathy. In: Acta Neuropathologica Communications. 2020 ; Vol. 8, No. 1.

Bibtex

@article{d08f0b0133354f62bdf343348484860b,
title = "Hippocampal tau oligomerization early in tau pathology coincides with a transient alteration of mitochondrial homeostasis and DNA repair in a mouse model of tauopathy",
abstract = "Insoluble intracellular aggregation of tau proteins into filaments and neurodegeneration are histopathological hallmarks of Alzheimer disease (AD) and other tauopathies. Recently, prefibrillar, soluble, oligomeric tau intermediates have emerged as relevant pathological tau species; however, the molecular mechanisms of neuronal responses to tau oligomers are not fully understood. Here, we show that hippocampal neurons in six-month-old transgenic mouse model of tauopathy, THY-Tau22, are enriched with oligomeric tau, contain elongated mitochondria, and display cellular stress, but no overt cytotoxicity compared to the control mice. The levels of several key mitochondrial proteins were markedly different between the THY-Tau22 and control mice hippocampi including the mitochondrial SIRT3, PINK1, ANT1 and the fission protein DRP1. DNA base excision repair (BER) is the primary defense system against oxidative DNA damage and it was elevated in six-month-old transgenic mice. DNA polymerase β, the key BER DNA polymerase, was enriched in the cytoplasm of hippocampal neurons in six-month-old transgenic mice and localized with and within mitochondria. Polβ also co-localized with mitochondria in human AD brains in neurons containing oligomeric tau. Most of these altered mitochondrial and DNA repair events were specific to the transgenic mice at 6 months of age and were not different from control mice at 12 months of age when tau pathology reaches its maximum and oligomeric forms of tau are no longer detectable. In summary, our data suggests that we have identified key cellular stress responses at early stages of tau pathology to preserve neuronal integrity and to promote survival. To our knowledge, this work provides the first description of multiple stress responses involving mitochondrial homeostasis and BER early during the progression of tau pathology, and represents an important advance in the etiopathogenesis of tauopathies.",
keywords = "Mitochondrial homeostasis, Oxidative stress, Polymerase beta, Tau oligomerization, Tauopathies",
author = "Jin Zheng and Mansour Akbari and Claire Schirmer and Reynaert, {Marie Line} and Anne Loyens and Bruno Lefebvre and Luc Bu{\'e}e and Croteau, {Deborah L.} and Galas, {Marie Christine} and Bohr, {Vilhelm A.}",
year = "2020",
doi = "10.1186/s40478-020-00896-8",
language = "English",
volume = "8",
journal = "Acta Neuropathologica Communications",
issn = "2051-5960",
publisher = "BioMed Central Ltd.",
number = "1",

}

RIS

TY - JOUR

T1 - Hippocampal tau oligomerization early in tau pathology coincides with a transient alteration of mitochondrial homeostasis and DNA repair in a mouse model of tauopathy

AU - Zheng, Jin

AU - Akbari, Mansour

AU - Schirmer, Claire

AU - Reynaert, Marie Line

AU - Loyens, Anne

AU - Lefebvre, Bruno

AU - Buée, Luc

AU - Croteau, Deborah L.

AU - Galas, Marie Christine

AU - Bohr, Vilhelm A.

PY - 2020

Y1 - 2020

N2 - Insoluble intracellular aggregation of tau proteins into filaments and neurodegeneration are histopathological hallmarks of Alzheimer disease (AD) and other tauopathies. Recently, prefibrillar, soluble, oligomeric tau intermediates have emerged as relevant pathological tau species; however, the molecular mechanisms of neuronal responses to tau oligomers are not fully understood. Here, we show that hippocampal neurons in six-month-old transgenic mouse model of tauopathy, THY-Tau22, are enriched with oligomeric tau, contain elongated mitochondria, and display cellular stress, but no overt cytotoxicity compared to the control mice. The levels of several key mitochondrial proteins were markedly different between the THY-Tau22 and control mice hippocampi including the mitochondrial SIRT3, PINK1, ANT1 and the fission protein DRP1. DNA base excision repair (BER) is the primary defense system against oxidative DNA damage and it was elevated in six-month-old transgenic mice. DNA polymerase β, the key BER DNA polymerase, was enriched in the cytoplasm of hippocampal neurons in six-month-old transgenic mice and localized with and within mitochondria. Polβ also co-localized with mitochondria in human AD brains in neurons containing oligomeric tau. Most of these altered mitochondrial and DNA repair events were specific to the transgenic mice at 6 months of age and were not different from control mice at 12 months of age when tau pathology reaches its maximum and oligomeric forms of tau are no longer detectable. In summary, our data suggests that we have identified key cellular stress responses at early stages of tau pathology to preserve neuronal integrity and to promote survival. To our knowledge, this work provides the first description of multiple stress responses involving mitochondrial homeostasis and BER early during the progression of tau pathology, and represents an important advance in the etiopathogenesis of tauopathies.

AB - Insoluble intracellular aggregation of tau proteins into filaments and neurodegeneration are histopathological hallmarks of Alzheimer disease (AD) and other tauopathies. Recently, prefibrillar, soluble, oligomeric tau intermediates have emerged as relevant pathological tau species; however, the molecular mechanisms of neuronal responses to tau oligomers are not fully understood. Here, we show that hippocampal neurons in six-month-old transgenic mouse model of tauopathy, THY-Tau22, are enriched with oligomeric tau, contain elongated mitochondria, and display cellular stress, but no overt cytotoxicity compared to the control mice. The levels of several key mitochondrial proteins were markedly different between the THY-Tau22 and control mice hippocampi including the mitochondrial SIRT3, PINK1, ANT1 and the fission protein DRP1. DNA base excision repair (BER) is the primary defense system against oxidative DNA damage and it was elevated in six-month-old transgenic mice. DNA polymerase β, the key BER DNA polymerase, was enriched in the cytoplasm of hippocampal neurons in six-month-old transgenic mice and localized with and within mitochondria. Polβ also co-localized with mitochondria in human AD brains in neurons containing oligomeric tau. Most of these altered mitochondrial and DNA repair events were specific to the transgenic mice at 6 months of age and were not different from control mice at 12 months of age when tau pathology reaches its maximum and oligomeric forms of tau are no longer detectable. In summary, our data suggests that we have identified key cellular stress responses at early stages of tau pathology to preserve neuronal integrity and to promote survival. To our knowledge, this work provides the first description of multiple stress responses involving mitochondrial homeostasis and BER early during the progression of tau pathology, and represents an important advance in the etiopathogenesis of tauopathies.

KW - Mitochondrial homeostasis

KW - Oxidative stress

KW - Polymerase beta

KW - Tau oligomerization

KW - Tauopathies

U2 - 10.1186/s40478-020-00896-8

DO - 10.1186/s40478-020-00896-8

M3 - Journal article

C2 - 32131898

AN - SCOPUS:85081225850

VL - 8

JO - Acta Neuropathologica Communications

JF - Acta Neuropathologica Communications

SN - 2051-5960

IS - 1

M1 - 25

ER -

ID: 239811529