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Alzheimer’s disease brain-derived tau-containing extracellular vesicles: Pathobiology and GABAergic neuronal transmission

Zhi Ruan, Dhruba Pathak, Srinidhi Venkatesan Kalavai, Asuka Yoshii-Kitahara, Satoshi Muraoka, Kayo Takamatsu-Yukawa, Nemil Bhatt, Jianqiao Hu, Yuzhi Wang, Samuel Hersh, Santhi Gorantla, Rakez Kayed, Howard E. Gendelman, Seiko Ikezu, Jennifer I. Luebke, View ORCID ProfileTsuneya Ikezu
doi: https://doi.org/10.1101/2020.03.15.992719
Zhi Ruan
1Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
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Dhruba Pathak
1Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
2Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA
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Srinidhi Venkatesan Kalavai
1Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
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Asuka Yoshii-Kitahara
1Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
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Satoshi Muraoka
1Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
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Kayo Takamatsu-Yukawa
1Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
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Nemil Bhatt
4Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA
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Jianqiao Hu
1Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
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Yuzhi Wang
1Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
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Samuel Hersh
1Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
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Santhi Gorantla
3Department of Pharmacology & Experimental Neurosciences, University of Nebraska Medical Center, Omaha 68198, NE, USA
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Rakez Kayed
4Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA
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Howard E. Gendelman
3Department of Pharmacology & Experimental Neurosciences, University of Nebraska Medical Center, Omaha 68198, NE, USA
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Seiko Ikezu
1Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
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Jennifer I. Luebke
2Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA
5Center for Systems Neuroscience, Boston University, Boston, MA 02118
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Tsuneya Ikezu
1Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
5Center for Systems Neuroscience, Boston University, Boston, MA 02118
6Department of Neurology and Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA 02118, USA
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  • ORCID record for Tsuneya Ikezu
  • For correspondence: tikezu@bu.edu
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Abstract

Extracellular vesicles (EVs) propagate tau pathology for Alzheimer’s disease (AD). How EV transmission influences AD are, nonetheless, poorly understood. To these ends, the physicochemical and molecular structure-function relationships of human brain-derived EVs, from AD and prodromal AD (pAD), were compared to non-demented controls (CTRL). AD EVs were shown to be significantly enriched in epitope-specific tau oligomers versus pAD or CTRL EVs assayed by dot-blot and atomic force microscopy tests. AD EVs were efficiently internalized by murine cortical neurons and transferred tau with higher aggregation potency than pAD and CTRL EVs. Strikingly, inoculation of tau-containing AD EVs into the outer molecular layer of the dentate gyrus induced tau propagation throughout the hippocampus. This was seen in 22 months-old C57BL/6 mice at 4.5 months post-injection by semiquantitative brain-wide immunohistochemistry tests with multiple anti-phospho-tau (p-tau) antibodies. Inoculation of the equal amount of tau from CTRL EVs or as oligomer or fibril-enriched fraction from the same AD donor showed little propagation. AD EVs induced tau accumulation in the hippocampus as oligomers or sarkosyl-insoluble proteins. Unexpectedly, p-tau cells were mostly GAD67+ GABAergic neurons and to a lesser extent, GluR2/3+ excitatory mossy cells, showing preferential EV-mediated GABAergic neuronal tau propagation. Whole-cell patch clamp recording of Cornu Ammonis (CA1) pyramidal cells showed significant reduction in the amplitude of spontaneous inhibitory post-synaptic currents. This was accompanied by reductions in c-fos+ GAD67+GABAergic neurons and GAD67+ GABAergic neuronal puncta surrounding pyramidal neurons in the CA1 region confirming reduced interneuronal projections. Our study posits a novel tau-associated pathological mechanism for brain-derived EVs.

Competing Interest Statement

The authors have declared no competing interest.

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Alzheimer’s disease brain-derived tau-containing extracellular vesicles: Pathobiology and GABAergic neuronal transmission
Zhi Ruan, Dhruba Pathak, Srinidhi Venkatesan Kalavai, Asuka Yoshii-Kitahara, Satoshi Muraoka, Kayo Takamatsu-Yukawa, Nemil Bhatt, Jianqiao Hu, Yuzhi Wang, Samuel Hersh, Santhi Gorantla, Rakez Kayed, Howard E. Gendelman, Seiko Ikezu, Jennifer I. Luebke, Tsuneya Ikezu
bioRxiv 2020.03.15.992719; doi: https://doi.org/10.1101/2020.03.15.992719
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Alzheimer’s disease brain-derived tau-containing extracellular vesicles: Pathobiology and GABAergic neuronal transmission
Zhi Ruan, Dhruba Pathak, Srinidhi Venkatesan Kalavai, Asuka Yoshii-Kitahara, Satoshi Muraoka, Kayo Takamatsu-Yukawa, Nemil Bhatt, Jianqiao Hu, Yuzhi Wang, Samuel Hersh, Santhi Gorantla, Rakez Kayed, Howard E. Gendelman, Seiko Ikezu, Jennifer I. Luebke, Tsuneya Ikezu
bioRxiv 2020.03.15.992719; doi: https://doi.org/10.1101/2020.03.15.992719

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