Neuronal exosome-derived human tau is toxic to recipient mouse neurons in vivo

Charisse N. Winston, Brent Aulston, Edward M. Rockenstein, Anthony Adame, Olga Prikhodko, Kishan N. Dave, Priyanka Mishra, Robert A. Rissman, Shauna H. Yuan

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Progressive accumulation of aggregation-prone proteins, amyloid-β (Aβ) and hyperphosphorylated tau (p-tau), are the defining hallmarks of Alzheimer's disease (AD). The mechanisms by which Aβ and p-tau are transmitted throughout the diseased brain are not yet completely understood. Interest in exosome research has grown dramatically over the past few years, specifically due to their potential role as biomarkers for staging of neurodegenerative diseases, including AD. Despite their diagnostic utility, the pathogenic potential of exosomes has yet to be fully elucidated. In this study, we use a series of recombinant tau antibodies to characterize a new model of human tau in vivo. Exosome suspensions derived from neuronally-differentiated, human induced pluripotent stem cells that express the repeat domain of tau P301L and V337M mutations (NiPSCEs) were injected into the wild-type mouse brain and pathological changes were characterized by immunostaining at one-(1 m) and two-month (2 m) post-injection. We found that tau inclusions were present throughout the brain at 2m post-injection, which were detectable using antibodies raised against full-length tau (K9JA) and misfolded tau (MC1). Furthermore, we found that phosphorylated tau immunoreactivity was elevated 1m post-injection, which was surprisingly normalized after 2m. Finally, we observed extensive degeneration of neuronal dendrites in both ipsilateral and contralateral hippocampi in NiPSCE treated mice. In summary, we demonstrate that exosomes are sufficient to cause longdistance propagation of tau pathology and neurodegeneration in vivo. These novel findings support an active role of exosomes in AD pathogenesis.

Original languageEnglish (US)
Pages (from-to)541-553
Number of pages13
JournalJournal of Alzheimer's Disease
Volume67
Issue number2
DOIs
StatePublished - 2019
Externally publishedYes

Bibliographical note

Funding Information:
We thank members of the Yuan and Rissman laboratories for technical assistance and critical reading of this manuscript. We thank Dr. Peter Davies (Albert Einstein College of Medicine) for donating antibodies MC-1 and PHF1. This work was supported by NIA grants AG057459, AG057469, AG051848, and

Publisher Copyright:
© 2019 IOS Press and the authors. All rights reserved.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

  • Alzheimer's disease
  • exosomes
  • induced pluripotent stem cells
  • tau propagation

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