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Neurobiol Dis. 2015 Oct;82:540-551. doi: 10.1016/j.nbd.2015.09.003. Epub 2015 Sep 16.

Prefibrillar Tau oligomers alter the nucleic acid protective function of Tau in hippocampal neurons in vivo.

Author information

1
Inserm, UMRS1172, JPArc, Alzheimer & Tauopathies, 1 rue Polonovski, 59045 Lille, France; Université de Lille, Faculté de Médecine, Lille, France; CHRU, Memory Clinic, Lille, France.
2
Department of Translational Science & Molecular Medicine, College of Human Medicine, Michigan State University, 333 Bostwick Ave. NE, Van Andel Institute, Grand Rapids, MI 49503, USA.
3
Department of Neurology, George and Cynthia Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, 301 University Blvd, Medical Research Building, Room 10.138C, Galveston, TX 77555-1045, USA; Department of Neuroscience & Cell Biology, George and Cynthia Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, 301 University Blvd, Medical Research Building, Room 10.138C, Galveston, TX 77555-1045, USA.
4
Inserm UMRS 1007, Université Paris Descartes, 45 rue des Saints Pères, 75006 Paris Cedex 06, France.
5
Inserm, UMRS1172, JPArc, Alzheimer & Tauopathies, 1 rue Polonovski, 59045 Lille, France; Université de Lille, Faculté de Médecine, Lille, France; CHRU, Memory Clinic, Lille, France. Electronic address: marie-christine.galas@inserm.fr.

Abstract

The accumulation of DNA and RNA oxidative damage is observed in cortical and hippocampal neurons from Alzheimer's disease (AD) brains at early stages of pathology. We recently reported that Tau is a key nuclear player in the protection of neuronal nucleic acid integrity in vivo under physiological conditions and hyperthermia, a strong inducer of oxidative stress. In a mouse model of tauopathy (THY-Tau22), we demonstrate that hyperthermia selectively induces nucleic acid oxidative damage and nucleic acid strand breaks in the nucleus and cytoplasm of hippocampal neurons that display early Tau phosphorylation but no Tau fibrils. Nucleic acid-damaged neurons were exclusively immunoreactive for prefibrillar Tau oligomers. A similar association between prefibrillar Tau oligomers and nucleic acid oxidative damage was observed in AD brains. Pretreatment with Methylene Blue (MB), a Tau aggregation inhibitor and a redox cycler, reduced hyperthermia-induced Tau oligomerization as well as nucleic acid damage. This study clearly highlights the existence of an early and critical time frame for hyperthermia-induced Tau oligomerization, which most likely occurs through increased oxidative stress, and nucleic acid vulnerability during the progression of Tau pathology. These results suggest that at early stages of AD, Tau oligomerization triggers the loss of the nucleic acid protective function of monomeric Tau. This study highlights the existence of a short therapeutic window in which to prevent the formation of pathological forms of Tau and their harmful consequences on nucleic acid integrity during the progression of Tau pathology.

KEYWORDS:

Alzheimer; DNA damage; Hyperthermia; Methylene Blue; Oxidative stress; RNA damage; Tau; Tau oligomers

PMID:
26385829
DOI:
10.1016/j.nbd.2015.09.003
[Indexed for MEDLINE]

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