Astrocytic expression of the Alzheimer’s disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models

Abstract ApoEε4 is a major genetic risk factor for Alzheimer’s disease (AD), a disease hallmarked by extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The presence of the ApoEε4 allele is associated with increased Aβ deposition and a role for ApoEε4 in the pot...

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Autores principales:	Angela Marie Jablonski, Lee Warren, Marija Usenovic, Heather Zhou, Jonathan Sugam, Sophie Parmentier-Batteur, Bhavya Voleti
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4fe83d6941c44b5bbe01ae4d30b636f0
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spelling	oai:doaj.org-article:4fe83d6941c44b5bbe01ae4d30b636f02021-12-02T12:15:02ZAstrocytic expression of the Alzheimer’s disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models10.1038/s41598-021-82901-12045-2322https://doaj.org/article/4fe83d6941c44b5bbe01ae4d30b636f02021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82901-1https://doaj.org/toc/2045-2322Abstract ApoEε4 is a major genetic risk factor for Alzheimer’s disease (AD), a disease hallmarked by extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The presence of the ApoEε4 allele is associated with increased Aβ deposition and a role for ApoEε4 in the potentiation of tau pathology has recently emerged. This study focused on comparing the effects of adeno-associated virus (AAV)-mediated overexpression of the three predominant human ApoE isoforms within astrocytes. The isoform-specific effects of human ApoE were evaluated within in vitro models of tau pathology within neuron/astrocyte co-cultures, as well as in a transgenic tau mouse model. Tau aggregation, accumulation, and phosphorylation were measured to determine if the three isoforms of human ApoE had differential effects on tau. Astrocytic overexpression of the human ApoEε4 allele increased phosphorylation and misfolding of overexpressed neuronal tau in multiple models, including the aggregation and accumulation of added tau oligomers, in an isoform-specific manner. The ability of ApoEε4 to increase tau aggregation could be inhibited by an ApoEε4-specific antibody. This study indicates that astrocytic expression of ApoEε4 can potentiate tau aggregation and phosphorylation within neurons and supports a gain of toxic function hypothesis for the effect of hApoEε4 on tau.Angela Marie JablonskiLee WarrenMarija UsenovicHeather ZhouJonathan SugamSophie Parmentier-BatteurBhavya VoletiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Angela Marie Jablonski Lee Warren Marija Usenovic Heather Zhou Jonathan Sugam Sophie Parmentier-Batteur Bhavya Voleti Astrocytic expression of the Alzheimer’s disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models
description	Abstract ApoEε4 is a major genetic risk factor for Alzheimer’s disease (AD), a disease hallmarked by extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The presence of the ApoEε4 allele is associated with increased Aβ deposition and a role for ApoEε4 in the potentiation of tau pathology has recently emerged. This study focused on comparing the effects of adeno-associated virus (AAV)-mediated overexpression of the three predominant human ApoE isoforms within astrocytes. The isoform-specific effects of human ApoE were evaluated within in vitro models of tau pathology within neuron/astrocyte co-cultures, as well as in a transgenic tau mouse model. Tau aggregation, accumulation, and phosphorylation were measured to determine if the three isoforms of human ApoE had differential effects on tau. Astrocytic overexpression of the human ApoEε4 allele increased phosphorylation and misfolding of overexpressed neuronal tau in multiple models, including the aggregation and accumulation of added tau oligomers, in an isoform-specific manner. The ability of ApoEε4 to increase tau aggregation could be inhibited by an ApoEε4-specific antibody. This study indicates that astrocytic expression of ApoEε4 can potentiate tau aggregation and phosphorylation within neurons and supports a gain of toxic function hypothesis for the effect of hApoEε4 on tau.
format	article
author	Angela Marie Jablonski Lee Warren Marija Usenovic Heather Zhou Jonathan Sugam Sophie Parmentier-Batteur Bhavya Voleti
author_facet	Angela Marie Jablonski Lee Warren Marija Usenovic Heather Zhou Jonathan Sugam Sophie Parmentier-Batteur Bhavya Voleti
author_sort	Angela Marie Jablonski
title	Astrocytic expression of the Alzheimer’s disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models
title_short	Astrocytic expression of the Alzheimer’s disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models
title_full	Astrocytic expression of the Alzheimer’s disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models
title_fullStr	Astrocytic expression of the Alzheimer’s disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models
title_full_unstemmed	Astrocytic expression of the Alzheimer’s disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models
title_sort	astrocytic expression of the alzheimer’s disease risk allele, apoeε4, potentiates neuronal tau pathology in multiple preclinical models
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4fe83d6941c44b5bbe01ae4d30b636f0
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Astrocytic expression of the Alzheimer’s disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models

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