Extracellular Vesicles Isolated from Familial Alzheimer’s Disease Neuronal Cultures Induce Aberrant Tau Phosphorylation in the Wild-Type Mouse Brain

Article type: Research Article

Authors: Aulston, Brent^a | Liu, Qing^a | Mante, Michael^a | Florio, Jazmin^a | Rissman, Robert A.^{a; b} | Yuan, Shauna H.^{a; *; 1}

Affiliations: [a] University of California, San Diego, Department of Neurosciences, La Jolla, CA, USA | [b] Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA

Correspondence: [*] Correspondence to: Shauna H. Yuan, Department of Neurosciences, University of California, San Diego, 9500 Gilman Dr., MTF Room 151, La Jolla, CA 92093-0624, USA. Tel.: +1 858 822 0626; E-mail: shyuan@ucsd.edu.

Note: [1] Current address: Department of Neurology, N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Twin Cities, 2101 6th St SE, WMBB, RM 5-178, Minneapolis, MN 55455, USA. Tel.: +1 612 625 6419; E-mail: syuan@umn.edu.

Abstract: Extracellular vesicles (EVs) are a heterogeneous group of secreted particles consisting of microvesicles, which are released by budding of the cellular membrane, and exosomes, which are secreted through exocytosis from multivesicular bodies. EV cargo consists of a wide range of proteins and nucleic acids that can be transferred between cells. Importantly, EVs may be pathogenically involved in neurodegenerative diseases such as Alzheimer’s disease (AD). While EVs derived from AD neurons have been found to be neurotoxic in vitro, little is known about the pathological consequences of AD EVs in vivo. Furthermore, although all known familial AD (fAD) mutations involve either amyloid-β protein precursor (AβPP) or the machinery that processes AβPP, hyperphosphorylation of the microtubule associated protein tau appears to play a critical role in fAD-associated neurodegeneration, and previous reports suggest EVs may propagate tau pathology in the AD brain. Therefore, we hypothesized that fAD EVs may have a mechanistic involvement in the development of fAD-associated tau pathology. To test this, we isolated EVs from iPSC-derived neuronal cultures generated from an fAD patient harboring a A246E mutation to presenilin-1 and stereotactically injected these EVs into the hippocampi of wild-type C57BL/6 mice. Five weeks after injection, mice were euthanized and pathology evaluated. Mice injected with fAD EVs displayed increased tau phosphorylation at multiple sites relative to PBS and non-disease control EV injected groups. Moreover, fAD EV injected hippocampi contained significantly more tau inclusions in the CA1 hippocampal neuronal field than controls. In total, these findings identify EVs as a potential mediator of fAD-associated tau dysregulation and warrant future studies to investigate the therapeutic potential of EV-targeted treatments for fAD.

Keywords: Alzheimer’s disease, C57BL/6, extracellular vesicles, induced pluripotent stem cells, tau, tauopathy

DOI: 10.3233/JAD-190656

Journal: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 575-585, 2019