Contribution of endogenous antibodies to learning deficits and astrocytosis in human P301S mutant tau transgenic mice

Abstract Antibodies have been explored extensively as a potential therapeutic for Alzheimer’s disease, where amyloid-β (Aβ) peptides and the tau protein deposit in patient brains. While the major focus of antibody-based therapy development was on Aβ, arguably with limited success in clinical trials,...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Julia van der Hoven, Annika van Hummel, Magdalena Przybyla, Prita R. Asih, Mehul Gajwani, Astrid F. Feiten, Yazi D. Ke, Arne Ittner, Janet van Eersel, Lars M. Ittner
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7542fd4f0b3143c8a94362ae7f8f1328
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:7542fd4f0b3143c8a94362ae7f8f1328
record_format	dspace
spelling	oai:doaj.org-article:7542fd4f0b3143c8a94362ae7f8f13282021-12-02T18:50:53ZContribution of endogenous antibodies to learning deficits and astrocytosis in human P301S mutant tau transgenic mice10.1038/s41598-020-70845-x2045-2322https://doaj.org/article/7542fd4f0b3143c8a94362ae7f8f13282020-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-70845-xhttps://doaj.org/toc/2045-2322Abstract Antibodies have been explored extensively as a potential therapeutic for Alzheimer’s disease, where amyloid-β (Aβ) peptides and the tau protein deposit in patient brains. While the major focus of antibody-based therapy development was on Aβ, arguably with limited success in clinical trials, targeting tau has become an emerging strategy, possibly extending therapies to dementias with isolated tau pathology. Interestingly, low titres of autoantibodies to pathological tau have been described in humans and transgenic mouse models, but their pathophysiological relevance remained elusive. Here, we used two independent approaches to deplete the B-cell lineage and hence antibody formation in human P301S mutant tau transgenic mice, TAU58/2. TAU58/2 mice were either crossed with the B-cell-deficient Ighm knockout line (muMT−/−) or treated with anti-CD20 antibodies that target B-cell precursors. In both models, B-cell depletion significantly reduced astrocytosis in TAU58/2 mice. Only when B-cells were absent throughout life, in TAU58/2.muMT−/− mice, were spatial learning deficits moderately aggravated while motor performance improved as compared to B-cell-competent TAU58/2 mice. This was associated with changes in brain region-specific tau solubility. No other relevant behavioural or neuropathological changes were observed in TAU58/2 mice in the absence of B-cells/antibodies. Taken together, our data suggests that the presence of antibodies throughout life contributes to astrocytosis in TAU58/2 mice and limits learning deficits, while other deficits and neuropathological changes appear to be independent of the presence of B-cells/antibodies.Julia van der HovenAnnika van HummelMagdalena PrzybylaPrita R. AsihMehul GajwaniAstrid F. FeitenYazi D. KeArne IttnerJanet van EerselLars M. IttnerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-16 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Julia van der Hoven Annika van Hummel Magdalena Przybyla Prita R. Asih Mehul Gajwani Astrid F. Feiten Yazi D. Ke Arne Ittner Janet van Eersel Lars M. Ittner Contribution of endogenous antibodies to learning deficits and astrocytosis in human P301S mutant tau transgenic mice
description	Abstract Antibodies have been explored extensively as a potential therapeutic for Alzheimer’s disease, where amyloid-β (Aβ) peptides and the tau protein deposit in patient brains. While the major focus of antibody-based therapy development was on Aβ, arguably with limited success in clinical trials, targeting tau has become an emerging strategy, possibly extending therapies to dementias with isolated tau pathology. Interestingly, low titres of autoantibodies to pathological tau have been described in humans and transgenic mouse models, but their pathophysiological relevance remained elusive. Here, we used two independent approaches to deplete the B-cell lineage and hence antibody formation in human P301S mutant tau transgenic mice, TAU58/2. TAU58/2 mice were either crossed with the B-cell-deficient Ighm knockout line (muMT−/−) or treated with anti-CD20 antibodies that target B-cell precursors. In both models, B-cell depletion significantly reduced astrocytosis in TAU58/2 mice. Only when B-cells were absent throughout life, in TAU58/2.muMT−/− mice, were spatial learning deficits moderately aggravated while motor performance improved as compared to B-cell-competent TAU58/2 mice. This was associated with changes in brain region-specific tau solubility. No other relevant behavioural or neuropathological changes were observed in TAU58/2 mice in the absence of B-cells/antibodies. Taken together, our data suggests that the presence of antibodies throughout life contributes to astrocytosis in TAU58/2 mice and limits learning deficits, while other deficits and neuropathological changes appear to be independent of the presence of B-cells/antibodies.
format	article
author	Julia van der Hoven Annika van Hummel Magdalena Przybyla Prita R. Asih Mehul Gajwani Astrid F. Feiten Yazi D. Ke Arne Ittner Janet van Eersel Lars M. Ittner
author_facet	Julia van der Hoven Annika van Hummel Magdalena Przybyla Prita R. Asih Mehul Gajwani Astrid F. Feiten Yazi D. Ke Arne Ittner Janet van Eersel Lars M. Ittner
author_sort	Julia van der Hoven
title	Contribution of endogenous antibodies to learning deficits and astrocytosis in human P301S mutant tau transgenic mice
title_short	Contribution of endogenous antibodies to learning deficits and astrocytosis in human P301S mutant tau transgenic mice
title_full	Contribution of endogenous antibodies to learning deficits and astrocytosis in human P301S mutant tau transgenic mice
title_fullStr	Contribution of endogenous antibodies to learning deficits and astrocytosis in human P301S mutant tau transgenic mice
title_full_unstemmed	Contribution of endogenous antibodies to learning deficits and astrocytosis in human P301S mutant tau transgenic mice
title_sort	contribution of endogenous antibodies to learning deficits and astrocytosis in human p301s mutant tau transgenic mice
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/7542fd4f0b3143c8a94362ae7f8f1328
work_keys_str_mv	AT juliavanderhoven contributionofendogenousantibodiestolearningdeficitsandastrocytosisinhumanp301smutanttautransgenicmice AT annikavanhummel contributionofendogenousantibodiestolearningdeficitsandastrocytosisinhumanp301smutanttautransgenicmice AT magdalenaprzybyla contributionofendogenousantibodiestolearningdeficitsandastrocytosisinhumanp301smutanttautransgenicmice AT pritarasih contributionofendogenousantibodiestolearningdeficitsandastrocytosisinhumanp301smutanttautransgenicmice AT mehulgajwani contributionofendogenousantibodiestolearningdeficitsandastrocytosisinhumanp301smutanttautransgenicmice AT astridffeiten contributionofendogenousantibodiestolearningdeficitsandastrocytosisinhumanp301smutanttautransgenicmice AT yazidke contributionofendogenousantibodiestolearningdeficitsandastrocytosisinhumanp301smutanttautransgenicmice AT arneittner contributionofendogenousantibodiestolearningdeficitsandastrocytosisinhumanp301smutanttautransgenicmice AT janetvaneersel contributionofendogenousantibodiestolearningdeficitsandastrocytosisinhumanp301smutanttautransgenicmice AT larsmittner contributionofendogenousantibodiestolearningdeficitsandastrocytosisinhumanp301smutanttautransgenicmice
_version_	1718377512877162496

Contribution of endogenous antibodies to learning deficits and astrocytosis in human P301S mutant tau transgenic mice

Ejemplares similares