Affiliations: [a]
Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA
| [b] Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA
Correspondence:
[*]
Correspondence to: Robert A. Rissman, Department of Neurosciences, UCSD School of Medicine, 9500 Gilman Drive, MTF 309 M/C 0624, La Jolla, CA 92093 0624, USA. Tel.: +1 858 246 0140; Fax: +1 858 246 0139; [email protected] and Shauna H. Yuan, Department of Neurosciences, UCSD School of Medicine, 9500 Gilman Drive, MTF 152 M/C 0624, La Jolla, CA 92093 0624, USA. Tel.: +1 858 822 0626; Fax: +1 858 822 2050; E-mail: [email protected].
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 2 m 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 1 m post-injection, which was surprisingly normalized after 2 m. 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 long-distance propagation of tau pathology and neurodegeneration in vivo. These novel findings support an active role of exosomes in AD pathogenesis.
Keywords: Alzheimer’s disease, exosomes, induced pluripotent stem cells, tau
propagation
