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Extracellular Vesicles Isolated from Familial Alzheimer's Disease Neuronal Cultures Induce Aberrant Tau Phosphorylation in the Wild-Type Mouse Brain.
J Alzheimers Dis. 2019; 72(2):575-585.JA

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.

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Authors+Show Affiliations

University of California, San Diego, Department of Neurosciences, La Jolla, CA, USA.

University of California, San Diego, Department of Neurosciences, La Jolla, CA, USA.

University of California, San Diego, Department of Neurosciences, La Jolla, CA, USA.

University of California, San Diego, Department of Neurosciences, La Jolla, CA, USA.

University of California, San Diego, Department of Neurosciences, La Jolla, CA, USA. Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA.

University of California, San Diego, Department of Neurosciences, La Jolla, CA, USA.

MeSH

Alzheimer DiseaseAnimalsCA1 Region, HippocampalCells, CulturedExtracellular VesiclesHumansInduced Pluripotent Stem CellsMiceMice, Inbred C57BLMutationNanoparticlesNeuronsPhosphorylationPresenilin-1Tauopathiestau Proteins

Pub Type(s)

Journal Article

Research Support, N.I.H., Extramural

Research Support, Non-U.S. Gov't

Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

31594233

Citation

Aulston, Brent, et al. "Extracellular Vesicles Isolated From Familial Alzheimer's Disease Neuronal Cultures Induce Aberrant Tau Phosphorylation in the Wild-Type Mouse Brain." Journal of Alzheimer's Disease : JAD, vol. 72, no. 2, 2019, pp. 575-585.

Aulston B, Liu Q, Mante M, et al. Extracellular Vesicles Isolated from Familial Alzheimer's Disease Neuronal Cultures Induce Aberrant Tau Phosphorylation in the Wild-Type Mouse Brain. J Alzheimers Dis. 2019;72(2):575-585.

Aulston, B., Liu, Q., Mante, M., Florio, J., Rissman, R. A., & Yuan, S. H. (2019). Extracellular Vesicles Isolated from Familial Alzheimer's Disease Neuronal Cultures Induce Aberrant Tau Phosphorylation in the Wild-Type Mouse Brain. Journal of Alzheimer's Disease : JAD, 72(2), 575-585. https://doi.org/10.3233/JAD-190656

Aulston B, et al. Extracellular Vesicles Isolated From Familial Alzheimer's Disease Neuronal Cultures Induce Aberrant Tau Phosphorylation in the Wild-Type Mouse Brain. J Alzheimers Dis. 2019;72(2):575-585. PubMed PMID: 31594233.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Extracellular Vesicles Isolated from Familial Alzheimer's Disease Neuronal Cultures Induce Aberrant Tau Phosphorylation in the Wild-Type Mouse Brain. AU - Aulston,Brent, AU - Liu,Qing, AU - Mante,Michael, AU - Florio,Jazmin, AU - Rissman,Robert A, AU - Yuan,Shauna H, PY - 2019/10/9/pubmed PY - 2020/11/18/medline PY - 2019/10/10/entrez KW - Alzheimer’s disease KW - C57BL/6 KW - extracellular vesicles KW - induced pluripotent stem cells KW - tau KW - tauopathy SP - 575 EP - 585 JF - Journal of Alzheimer's disease : JAD JO - J Alzheimers Dis VL - 72 IS - 2 N2 - 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. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/31594233/Extracellular_Vesicles_Isolated_from_Familial_Alzheimer's_Disease_Neuronal_Cultures_Induce_Aberrant_Tau_Phosphorylation_in_the_Wild_Type_Mouse_Brain_ DB - PRIME DP - Unbound Medicine ER -