TY - JOUR
T1 - Neuronal exosome-derived human tau is toxic to recipient mouse neurons in vivo
AU - Winston, Charisse N.
AU - Aulston, Brent
AU - Rockenstein, Edward M.
AU - Adame, Anthony
AU - Prikhodko, Olga
AU - Dave, Kishan N.
AU - Mishra, Priyanka
AU - Rissman, Robert A.
AU - Yuan, Shauna H.
N1 - Publisher Copyright:
© 2019 IOS Press and the authors. All rights reserved.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - exosomes
KW - induced pluripotent stem cells
KW - tau propagation
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U2 - 10.3233/JAD-180776
DO - 10.3233/JAD-180776
M3 - Article
C2 - 30584143
AN - SCOPUS:85060586246
SN - 1387-2877
VL - 67
SP - 541
EP - 553
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 2
ER -