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Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β

In Alzheimer's disease (AD), deposition of pathological tau and amyloid-β (Aβ) drive synaptic loss and cognitive decline. The injection of misfolded tau aggregates extracted from human AD brains drives templated spreading of tau pathology within WT mouse brain. Here, we assessed the impact of A...

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Autores principales: Nies, Sarah Helena, Takahashi, Hideyuki, Herber, Charlotte S., Huttner, Anita, Chase, Alison, Strittmatter, Stephen M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477193/
https://www.ncbi.nlm.nih.gov/pubmed/34480901
http://dx.doi.org/10.1016/j.jbc.2021.101159
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author Nies, Sarah Helena
Takahashi, Hideyuki
Herber, Charlotte S.
Huttner, Anita
Chase, Alison
Strittmatter, Stephen M.
author_facet Nies, Sarah Helena
Takahashi, Hideyuki
Herber, Charlotte S.
Huttner, Anita
Chase, Alison
Strittmatter, Stephen M.
author_sort Nies, Sarah Helena
collection PubMed
description In Alzheimer's disease (AD), deposition of pathological tau and amyloid-β (Aβ) drive synaptic loss and cognitive decline. The injection of misfolded tau aggregates extracted from human AD brains drives templated spreading of tau pathology within WT mouse brain. Here, we assessed the impact of Aβ copathology, of deleting loci known to modify AD risk (Ptk2b, Grn, and Tmem106b) and of pharmacological intervention with an Fyn kinase inhibitor on tau spreading after injection of AD tau extracts. The density and spreading of tau inclusions triggered by human tau seed were unaltered in the hippocampus and cortex of APPswe/PSEN1ΔE9 transgenic and App(NL-F/NL-F) knock-in mice. In mice with human tau sequence replacing mouse tau, template matching enhanced neuritic tau burden. Human AD brain tau-enriched preparations contained aggregated Aβ, and the Aβ coinjection caused a redistribution of Aβ aggregates in mutant AD model mice. The injection-induced Aβ phenotype was spatially distinct from tau accumulation and could be ameliorated by depleting Aβ from tau extracts. These data suggest that Aβ and tau pathologies propagate by largely independent mechanisms after their initial formation. Altering the activity of the Fyn and Pyk2 (Ptk2b) kinases involved in Aβ-oligomer–induced signaling, or deleting expression of the progranulin and TMEM106B lysosomal proteins, did not alter the somatic tau inclusion burden or spreading. However, mouse aging had a prominent effect to increase the accumulation of neuritic tau after injection of human AD tau seeds into WT mice. These studies refine our knowledge of factors capable of modulating tau spreading.
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spelling pubmed-84771932021-10-01 Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β Nies, Sarah Helena Takahashi, Hideyuki Herber, Charlotte S. Huttner, Anita Chase, Alison Strittmatter, Stephen M. J Biol Chem Research Article In Alzheimer's disease (AD), deposition of pathological tau and amyloid-β (Aβ) drive synaptic loss and cognitive decline. The injection of misfolded tau aggregates extracted from human AD brains drives templated spreading of tau pathology within WT mouse brain. Here, we assessed the impact of Aβ copathology, of deleting loci known to modify AD risk (Ptk2b, Grn, and Tmem106b) and of pharmacological intervention with an Fyn kinase inhibitor on tau spreading after injection of AD tau extracts. The density and spreading of tau inclusions triggered by human tau seed were unaltered in the hippocampus and cortex of APPswe/PSEN1ΔE9 transgenic and App(NL-F/NL-F) knock-in mice. In mice with human tau sequence replacing mouse tau, template matching enhanced neuritic tau burden. Human AD brain tau-enriched preparations contained aggregated Aβ, and the Aβ coinjection caused a redistribution of Aβ aggregates in mutant AD model mice. The injection-induced Aβ phenotype was spatially distinct from tau accumulation and could be ameliorated by depleting Aβ from tau extracts. These data suggest that Aβ and tau pathologies propagate by largely independent mechanisms after their initial formation. Altering the activity of the Fyn and Pyk2 (Ptk2b) kinases involved in Aβ-oligomer–induced signaling, or deleting expression of the progranulin and TMEM106B lysosomal proteins, did not alter the somatic tau inclusion burden or spreading. However, mouse aging had a prominent effect to increase the accumulation of neuritic tau after injection of human AD tau seeds into WT mice. These studies refine our knowledge of factors capable of modulating tau spreading. American Society for Biochemistry and Molecular Biology 2021-09-02 /pmc/articles/PMC8477193/ /pubmed/34480901 http://dx.doi.org/10.1016/j.jbc.2021.101159 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Nies, Sarah Helena
Takahashi, Hideyuki
Herber, Charlotte S.
Huttner, Anita
Chase, Alison
Strittmatter, Stephen M.
Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β
title Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β
title_full Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β
title_fullStr Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β
title_full_unstemmed Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β
title_short Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β
title_sort spreading of alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477193/
https://www.ncbi.nlm.nih.gov/pubmed/34480901
http://dx.doi.org/10.1016/j.jbc.2021.101159
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