Cargando…

Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau

Insoluble fibrillar tau, the primary constituent of neurofibrillary tangles, has traditionally been thought to be the biologically active, toxic form of tau mediating neurodegeneration in Alzheimer’s disease. More recent studies have implicated soluble oligomeric tau species, referred to as high mol...

Descripción completa

Detalles Bibliográficos
Autores principales: Mate De Gerando, Anastasie, Welikovitch, Lindsay A., Khasnavis, Anita, Commins, Caitlin, Glynn, Calina, Chun, Joshua E., Perbet, Romain, Hyman, Bradley T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10329061/
https://www.ncbi.nlm.nih.gov/pubmed/37341831
http://dx.doi.org/10.1007/s00401-023-02600-1
_version_ 1785069943131209728
author Mate De Gerando, Anastasie
Welikovitch, Lindsay A.
Khasnavis, Anita
Commins, Caitlin
Glynn, Calina
Chun, Joshua E.
Perbet, Romain
Hyman, Bradley T.
author_facet Mate De Gerando, Anastasie
Welikovitch, Lindsay A.
Khasnavis, Anita
Commins, Caitlin
Glynn, Calina
Chun, Joshua E.
Perbet, Romain
Hyman, Bradley T.
author_sort Mate De Gerando, Anastasie
collection PubMed
description Insoluble fibrillar tau, the primary constituent of neurofibrillary tangles, has traditionally been thought to be the biologically active, toxic form of tau mediating neurodegeneration in Alzheimer’s disease. More recent studies have implicated soluble oligomeric tau species, referred to as high molecular weight (HMW), due to their properties on size-exclusion chromatography, in tau propagation across neural systems. These two forms of tau have never been directly compared. We prepared sarkosyl-insoluble and HMW tau from the frontal cortex of Alzheimer patients and compared their properties using a variety of biophysical and bioactivity assays. Sarkosyl-insoluble fibrillar tau comprises abundant paired-helical filaments (PHF) as quantified by electron microscopy (EM) and is more resistant to proteinase K, compared to HMW tau, which is mostly in an oligomeric form. Sarkosyl-insoluble and HMW tau are nearly equivalent in potency in HEK cell bioactivity assay for seeding aggregates, and their injection reveals similar local uptake into hippocampal neurons in PS19 Tau transgenic mice. However, the HMW preparation appears to be far more potent in inducing a glial response including Clec7a-positive rod microglia in the absence of neurodegeneration or synapse loss and promotes more rapid propagation of misfolded tau to distal, anatomically connected regions, such as entorhinal and perirhinal cortices. These data suggest that soluble HMW tau has similar properties to fibrillar sarkosyl-insoluble tau with regard to tau seeding potential, but may be equal or even more bioactive with respect to propagation across neural systems and activation of glial responses, both relevant to tau-related Alzheimer phenotypes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-023-02600-1.
format Online
Article
Text
id pubmed-10329061
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Springer Berlin Heidelberg
record_format MEDLINE/PubMed
spelling pubmed-103290612023-07-09 Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau Mate De Gerando, Anastasie Welikovitch, Lindsay A. Khasnavis, Anita Commins, Caitlin Glynn, Calina Chun, Joshua E. Perbet, Romain Hyman, Bradley T. Acta Neuropathol Original Paper Insoluble fibrillar tau, the primary constituent of neurofibrillary tangles, has traditionally been thought to be the biologically active, toxic form of tau mediating neurodegeneration in Alzheimer’s disease. More recent studies have implicated soluble oligomeric tau species, referred to as high molecular weight (HMW), due to their properties on size-exclusion chromatography, in tau propagation across neural systems. These two forms of tau have never been directly compared. We prepared sarkosyl-insoluble and HMW tau from the frontal cortex of Alzheimer patients and compared their properties using a variety of biophysical and bioactivity assays. Sarkosyl-insoluble fibrillar tau comprises abundant paired-helical filaments (PHF) as quantified by electron microscopy (EM) and is more resistant to proteinase K, compared to HMW tau, which is mostly in an oligomeric form. Sarkosyl-insoluble and HMW tau are nearly equivalent in potency in HEK cell bioactivity assay for seeding aggregates, and their injection reveals similar local uptake into hippocampal neurons in PS19 Tau transgenic mice. However, the HMW preparation appears to be far more potent in inducing a glial response including Clec7a-positive rod microglia in the absence of neurodegeneration or synapse loss and promotes more rapid propagation of misfolded tau to distal, anatomically connected regions, such as entorhinal and perirhinal cortices. These data suggest that soluble HMW tau has similar properties to fibrillar sarkosyl-insoluble tau with regard to tau seeding potential, but may be equal or even more bioactive with respect to propagation across neural systems and activation of glial responses, both relevant to tau-related Alzheimer phenotypes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-023-02600-1. Springer Berlin Heidelberg 2023-06-21 2023 /pmc/articles/PMC10329061/ /pubmed/37341831 http://dx.doi.org/10.1007/s00401-023-02600-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Paper
Mate De Gerando, Anastasie
Welikovitch, Lindsay A.
Khasnavis, Anita
Commins, Caitlin
Glynn, Calina
Chun, Joshua E.
Perbet, Romain
Hyman, Bradley T.
Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau
title Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau
title_full Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau
title_fullStr Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau
title_full_unstemmed Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau
title_short Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau
title_sort tau seeding and spreading in vivo is supported by both ad-derived fibrillar and oligomeric tau
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10329061/
https://www.ncbi.nlm.nih.gov/pubmed/37341831
http://dx.doi.org/10.1007/s00401-023-02600-1
work_keys_str_mv AT matedegerandoanastasie tauseedingandspreadinginvivoissupportedbybothadderivedfibrillarandoligomerictau
AT welikovitchlindsaya tauseedingandspreadinginvivoissupportedbybothadderivedfibrillarandoligomerictau
AT khasnavisanita tauseedingandspreadinginvivoissupportedbybothadderivedfibrillarandoligomerictau
AT comminscaitlin tauseedingandspreadinginvivoissupportedbybothadderivedfibrillarandoligomerictau
AT glynncalina tauseedingandspreadinginvivoissupportedbybothadderivedfibrillarandoligomerictau
AT chunjoshuae tauseedingandspreadinginvivoissupportedbybothadderivedfibrillarandoligomerictau
AT perbetromain tauseedingandspreadinginvivoissupportedbybothadderivedfibrillarandoligomerictau
AT hymanbradleyt tauseedingandspreadinginvivoissupportedbybothadderivedfibrillarandoligomerictau