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Article ; Online: An In Vitro Model for Studying Tau Aggregation Using Lentiviral-mediated Transduction of Human Neurons.

Aulston, Brent / Liu, Qing / Reilly, Patrick / Yuan, Shauna H

Journal of visualized experiments : JoVE

2019 , Issue 147

Abstract: Aberrant aggregation of the protein tau is pathogenically involved in a number of neurodegenerative diseases, including Alzheimer's disease (AD). Although mouse models of tauopathy have provided a valuable resource for investigating the neurotoxic ... ...

Abstract	Aberrant aggregation of the protein tau is pathogenically involved in a number of neurodegenerative diseases, including Alzheimer's disease (AD). Although mouse models of tauopathy have provided a valuable resource for investigating the neurotoxic mechanisms of aggregated tau, it is becoming increasingly apparent that, due to interspecies differences in neurophysiology, the mouse brain is unsuitable for modeling the human condition. Advances in cell culture methods have made human neuronal cultures accessible for experimental use in vitro and have aided in the development of neurotherapeutics. However, despite the adaptation of human neuronal cell cultures, in vitro models of human tauopathy are not yet widely available. This protocol describes a cellular model of tau aggregation in which human neurons are transduced with lentiviral-derived vectors that code for pathogenically mutated tau fused to a yellow fluorescent protein (YFP) reporter. Transduced cultures produce tau aggregates that stain positively for thioflavin and display markers of neurotoxicity, such as decreased axonal length and increased lysosomal volume. This procedure may be a useful and cost-effective model for studying human tauopathies.
MeSH term(s)	Alzheimer Disease/physiopathology ; Animals ; Brain/pathology ; Disease Models, Animal ; Humans ; In Vitro Techniques ; Mice ; Neurons/metabolism ; tau Proteins/metabolism
Chemical Substances	tau Proteins
Language	English
Publishing date	2019-05-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/59433
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: An in vitro model for studying tau aggregation using lentiviral-mediated transduction of human neurons

Aulston, Brent / Liu, Qing / Reilly, Patrick / Yuan, Shauna H

Journal of visualized experiments. 2019 May 23, , no. 147

2019

Abstract: Aberrant aggregation of the protein tau is pathogenically involved in a number of neurodegenerative diseases, including Alzheimer’s disease (AD). Although mouse models of tauopathy have provided a valuable resource for investigating the neurotoxic ... ...

Abstract	Aberrant aggregation of the protein tau is pathogenically involved in a number of neurodegenerative diseases, including Alzheimer’s disease (AD). Although mouse models of tauopathy have provided a valuable resource for investigating the neurotoxic mechanisms of aggregated tau, it is becoming increasingly apparent that, due to interspecies differences in neurophysiology, the mouse brain is unsuitable for modeling the human condition. Advances in cell culture methods have made human neuronal cultures accessible for experimental use in vitro and have aided in the development of neurotherapeutics. However, despite the adaptation of human neuronal cell cultures, in vitro models of human tauopathy are not yet widely available. This protocol describes a cellular model of tau aggregation in which human neurons are transduced with lentiviral-derived vectors that code for pathogenically mutated tau fused to a yellow fluorescent protein (YFP) reporter. Transduced cultures produce tau aggregates that stain positively for thioflavin and display markers of neurotoxicity, such as decreased axonal length and increased lysosomal volume. This procedure may be a useful and cost-effective model for studying human tauopathies.
Keywords	Alzheimer disease ; animal models ; brain ; cell culture ; cost effectiveness ; humans ; mice ; neurodegenerative diseases ; neurons ; neurophysiology ; neurotoxicity ; yellow fluorescent protein
Language	English
Dates of publication	2019-0523
Size	p. e59433.
Publishing place	Journal of Visualized Experiments
Document type	Article
ISSN	1940-087X
DOI	10.3791/59433
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Extracellular Vesicles Isolated from Familial Alzheimer's Disease Neuronal Cultures Induce Aberrant Tau Phosphorylation in the Wild-Type Mouse Brain.

Aulston, Brent / Liu, Qing / Mante, Michael / Florio, Jazmin / Rissman, Robert A / Yuan, Shauna H

Journal of Alzheimer's disease : JAD

2019 Volume 72, Issue 2, Page(s) 575–585

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 ... ...

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.
MeSH term(s)	Alzheimer Disease/metabolism ; Animals ; CA1 Region, Hippocampal/cytology ; CA1 Region, Hippocampal/metabolism ; Cells, Cultured ; Extracellular Vesicles ; Humans ; Induced Pluripotent Stem Cells ; Mice ; Mice, Inbred C57BL ; Mutation/genetics ; Nanoparticles ; Neurons/metabolism ; Phosphorylation ; Presenilin-1/genetics ; Tauopathies/metabolism ; Tauopathies/pathology ; tau Proteins/metabolism
Chemical Substances	Presenilin-1 ; presenilin 1, mouse ; tau Proteins
Language	English
Publishing date	2019-10-08
Publishing country	Netherlands
Document type	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.
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-190656
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Zs.A 6084: Show issues

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Article ; Online: Serine-129 phosphorylation of α-synuclein is an activity-dependent trigger for physiologic protein-protein interactions and synaptic function.

Parra-Rivas, Leonardo A / Madhivanan, Kayalvizhi / Aulston, Brent D / Wang, Lina / Prakashchand, Dube Dheeraj / Boyer, Nicholas P / Saia-Cereda, Veronica M / Branes-Guerrero, Kristen / Pizzo, Donald P / Bagchi, Pritha / Sundar, V S / Tang, Yong / Das, Utpal / Scott, David A / Rangamani, Padmini / Ogawa, Yuki / Subhojit Roy

Neuron

2023 Volume 111, Issue 24, Page(s) 4006–4023.e10

Abstract: Phosphorylation of α-synuclein at the serine-129 site (α-syn Ser129P) is an established pathologic hallmark of synucleinopathies and a therapeutic target. In physiologic states, only a fraction of α-syn is phosphorylated at this site, and most studies ... ...

Abstract	Phosphorylation of α-synuclein at the serine-129 site (α-syn Ser129P) is an established pathologic hallmark of synucleinopathies and a therapeutic target. In physiologic states, only a fraction of α-syn is phosphorylated at this site, and most studies have focused on the pathologic roles of this post-translational modification. We found that unlike wild-type (WT) α-syn, which is widely expressed throughout the brain, the overall pattern of α-syn Ser129P is restricted, suggesting intrinsic regulation. Surprisingly, preventing Ser129P blocked activity-dependent synaptic attenuation by α-syn-thought to reflect its normal function. Exploring mechanisms, we found that neuronal activity augments Ser129P, which is a trigger for protein-protein interactions that are necessary for mediating α-syn function at the synapse. AlphaFold2-driven modeling and membrane-binding simulations suggest a scenario where Ser129P induces conformational changes that facilitate interactions with binding partners. Our experiments offer a new conceptual platform for investigating the role of Ser129 in synucleinopathies, with implications for drug development.
MeSH term(s)	Humans ; alpha-Synuclein/metabolism ; Phosphorylation ; Parkinson Disease/metabolism ; Synucleinopathies ; Serine/metabolism
Chemical Substances	alpha-Synuclein ; Serine (452VLY9402)
Language	English
Publishing date	2023-12-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2023.11.020
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Zs.A 2496: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 92: Show issues

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Article ; Online: Secreted amyloid precursor protein alpha activates neuronal insulin receptors and prevents diabetes-induced encephalopathy.

Aulston, Brent D / Schapansky, Jason / Huang, YaWen / Odero, Gary L / Glazner, Gordon W

Experimental neurology

2018 Volume 303, Page(s) 29–37

Abstract: Secreted amyloid precursor protein alpha (sAPPα) is a potent neurotrophin in the CNS but a dedicated receptor has not been found. However, protein interactions involving amyloid beta (Aβ), a peptide cleaved from the same parent peptide as sAPPα, indicate ...

Abstract	Secreted amyloid precursor protein alpha (sAPPα) is a potent neurotrophin in the CNS but a dedicated receptor has not been found. However, protein interactions involving amyloid beta (Aβ), a peptide cleaved from the same parent peptide as sAPPα, indicate that insulin receptors (IRs) could be a target of amyloid peptides. In this study, in vitro analysis of cortical neuronal cultures revealed that exogenous sAPPα increased IR phosphorylation in the absence of insulin. Furthermore, in an APP overexpressing mouse model, sAPPα bound IRs in the cortex with significantly greater binding in hypoinsulinemic animals. To further examine the effects of sAPPα on the diabetic brain, we next rendered sAPPα overexpressing mice insulin depleted and found that sAPPα blocked aberrant tau phosphorylation (T231) in cortical tissue after 16 weeks diabetes. sAPPα overexpression also prevented hyperphosphorylation of AKT/GSK3 and activation of the unfolded protein response (UPR). In total, these data show sAPPα binds and activates neuronal IRs and that sAPPα has a protective effect on diabetic brain tissue.
MeSH term(s)	Amyloid beta-Peptides/pharmacology ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Amyloid beta-Protein Precursor/pharmacology ; Animals ; Brain Diseases/etiology ; Brain Diseases/prevention & control ; Cells, Cultured ; Diabetes Mellitus, Experimental/complications ; Disease Models, Animal ; Embryo, Mammalian ; Glycated Hemoglobin A/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation/genetics ; Neurons/drug effects ; Neurons/metabolism ; Peptide Fragments/genetics ; Peptide Fragments/metabolism ; Peptide Fragments/pharmacology ; Phosphorylation/physiology ; Protein Binding/physiology ; Receptor, Insulin/metabolism ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Unfolded Protein Response/genetics ; tau Proteins/metabolism
Chemical Substances	APP protein, human ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Glycated Hemoglobin A ; Peptide Fragments ; amyloid beta-protein (1-42) ; tau Proteins ; Receptor, Insulin (EC 2.7.10.1)
Language	English
Publishing date	2018-02-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	207148-4
ISSN	1090-2430 ; 0014-4886
ISSN (online)	1090-2430
ISSN	0014-4886
DOI	10.1016/j.expneurol.2018.01.013
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Zs.A 184: Show issues

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Article ; Online: Mutant Presenilin 1 Dysregulates Exosomal Proteome Cargo Produced by Human-Induced Pluripotent Stem Cell Neurons.

Podvin, Sonia / Jones, Alexander / Liu, Qing / Aulston, Brent / Mosier, Charles / Ames, Janneca / Winston, Charisse / Lietz, Christopher B / Jiang, Zhenze / O'Donoghue, Anthony J / Ikezu, Tsuneya / Rissman, Robert A / Yuan, Shauna H / Hook, Vivian

ACS omega

2021 Volume 6, Issue 20, Page(s) 13033–13056

Abstract: The accumulation and propagation of hyperphosphorylated tau (p-Tau) is a neuropathological hallmark occurring with neurodegeneration of Alzheimer's disease (AD). Extracellular vesicles, exosomes, have been shown to initiate tau propagation in the brain. ... ...

Abstract	The accumulation and propagation of hyperphosphorylated tau (p-Tau) is a neuropathological hallmark occurring with neurodegeneration of Alzheimer's disease (AD). Extracellular vesicles, exosomes, have been shown to initiate tau propagation in the brain. Notably, exosomes from human-induced pluripotent stem cell (iPSC) neurons expressing the AD familial A246E mutant form of presenilin 1 (mPS1) are capable of inducing tau deposits in the mouse brain after
Language	English
Publishing date	2021-05-13
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.1c00660
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Article ; Online: Diminished Neuronal ESCRT-0 Function Exacerbates AMPA Receptor Derangement and Accelerates Prion-Induced Neurodegeneration.

The Journal of neuroscience : the official journal of the Society for Neuroscience

2023 Volume 43, Issue 21, Page(s) 3970–3984

Abstract: Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the multivesicular body (MVB) and are routed for degradation in lysosomes or for release in ...

Abstract	Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the multivesicular body (MVB) and are routed for degradation in lysosomes or for release in exosomes, yet how prions impact proteostatic pathways is unclear. We found that prion-affected human and mouse brain showed a marked reduction in Hrs and STAM1 (ESCRT-0), which route ubiquitinated membrane proteins from early endosomes into MVBs. To determine how the reduction in ESCRT-0 impacts prion conversion and cellular toxicity
MeSH term(s)	Male ; Female ; Mice ; Humans ; Animals ; Prions/metabolism ; Prion Proteins/metabolism ; Receptors, AMPA/metabolism ; Neurons/metabolism ; Prion Diseases/metabolism ; Prion Diseases/pathology ; Neurodegenerative Diseases/metabolism ; Endosomal Sorting Complexes Required for Transport/metabolism
Chemical Substances	Prions ; Prion Proteins ; Receptors, AMPA ; Endosomal Sorting Complexes Required for Transport
Language	English
Publishing date	2023-04-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.1878-22.2023
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Zs.A 1668: Show issues

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Article ; Online: Dysregulation of Exosome Cargo by Mutant Tau Expressed in Human-induced Pluripotent Stem Cell (iPSC) Neurons Revealed by Proteomics Analyses.

Podvin, Sonia / Jones, Alexander / Liu, Qing / Aulston, Brent / Ransom, Linnea / Ames, Janneca / Shen, Gloria / Lietz, Christopher B / Jiang, Zhenze / O'Donoghue, Anthony J / Winston, Charisse / Ikezu, Tsuneya / Rissman, Robert A / Yuan, Shauna / Hook, Vivian

Molecular & cellular proteomics : MCP

2020 Volume 19, Issue 6, Page(s) 1017–1034

Abstract: Accumulation and propagation of hyperphosphorylated Tau (p-Tau) is a common neuropathological hallmark associated with neurodegeneration of Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and related ... ...

Abstract	Accumulation and propagation of hyperphosphorylated Tau (p-Tau) is a common neuropathological hallmark associated with neurodegeneration of Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and related tauopathies. Extracellular vesicles, specifically exosomes, have recently been demonstrated to participate in mediating Tau propagation in brain. Exosomes produced by human induced pluripotent stem cell (iPSC)-derived neurons expressing mutant Tau (mTau), containing the P301L and V337M Tau mutations of FTDP-17, possess the ability to propagate p-Tau pathology after injection into mouse brain. To gain an understanding of the mTau exosome cargo involved in Tau pathogenesis, these pathogenic exosomes were analyzed by proteomics and bioinformatics. The data showed that mTau expression dysregulates the exosome proteome to result in 1) proteins uniquely present only in mTau, and not control exosomes, 2) the absence of proteins in mTau exosomes, uniquely present in control exosomes, and 3) shared proteins which were significantly upregulated or downregulated in mTau compared with control exosomes. Notably, mTau exosomes (not control exosomes) contain ANP32A (also known as I1PP2A), an endogenous inhibitor of the PP2A phosphatase which regulates the phosphorylation state of p-Tau. Several of the mTau exosome-specific proteins have been shown to participate in AD mechanisms involving lysosomes, inflammation, secretases, and related processes. Furthermore, the mTau exosomes lacked a substantial portion of proteins present in control exosomes involved in pathways of localization, vesicle transport, and protein binding functions. The shared proteins present in both mTau and control exosomes represented exosome functions of vesicle-mediated transport, exocytosis, and secretion processes. These data illustrate mTau as a dynamic regulator of the biogenesis of exosomes to result in acquisition, deletion, and up- or downregulation of protein cargo to result in pathogenic mTau exosomes capable of
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Animals ; Brain/metabolism ; Brain/pathology ; Cells, Cultured ; Chromatography, Liquid ; Computational Biology ; Exosomes/metabolism ; Exosomes/pathology ; Gene Ontology ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Mutation ; Neurons/metabolism ; Neurons/pathology ; Nuclear Proteins/metabolism ; Phosphorylation ; Protein Binding ; Protein Interaction Maps ; Protein Phosphatase 2/antagonists & inhibitors ; Protein Phosphatase 2/metabolism ; Proteomics ; RNA-Binding Proteins/metabolism ; Tandem Mass Spectrometry ; tau Proteins/genetics ; tau Proteins/metabolism
Chemical Substances	ANP32A protein, human ; MAPT protein, human ; Nuclear Proteins ; RNA-Binding Proteins ; tau Proteins ; Protein Phosphatase 2 (EC 3.1.3.16)
Language	English
Publishing date	2020-04-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
DOI	10.1074/mcp.RA120.002079
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Zs.A 5599: Show issues

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Article ; Online: Neuronal Exosome-Derived Human Tau is Toxic to Recipient Mouse Neurons in vivo.

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

Journal of Alzheimer's disease : JAD

2018 Volume 67, Issue 2, Page(s) 541–553

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 ...

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.
MeSH term(s)	Animals ; Antibodies/chemistry ; Brain Chemistry/genetics ; Dendrites/pathology ; Exosomes/chemistry ; Female ; Hippocampus/pathology ; Humans ; Immunohistochemistry ; Induced Pluripotent Stem Cells ; Mice ; Mice, Inbred C57BL ; Mutation/genetics ; Neurons/chemistry ; Neurons/drug effects ; Phosphorylation ; Proteostasis Deficiencies/pathology ; tau Proteins/genetics ; tau Proteins/immunology ; tau Proteins/toxicity
Chemical Substances	Antibodies ; MAPT protein, human ; tau Proteins
Language	English
Publishing date	2018-12-26
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-180776
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Zs.A 6084: Show issues

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