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Loss of presenilin function enhances tau phosphorylation and aggregation in mice

Mutations in the presenilin (PS/PSEN) genes encoding the catalytic components of γ-secretase accelerate amyloid-β (Aβ) and tau pathologies in familial Alzheimer’s disease (AD). Although the mechanisms by which these mutations affect Aβ are well defined, the precise role PS/γ-secretase on tau patholo...

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Autores principales: Soto-Faguás, Carlos M., Sanchez-Molina, Paula, Saura, Carlos A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482568/
https://www.ncbi.nlm.nih.gov/pubmed/34593029
http://dx.doi.org/10.1186/s40478-021-01259-7
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author Soto-Faguás, Carlos M.
Sanchez-Molina, Paula
Saura, Carlos A.
author_facet Soto-Faguás, Carlos M.
Sanchez-Molina, Paula
Saura, Carlos A.
author_sort Soto-Faguás, Carlos M.
collection PubMed
description Mutations in the presenilin (PS/PSEN) genes encoding the catalytic components of γ-secretase accelerate amyloid-β (Aβ) and tau pathologies in familial Alzheimer’s disease (AD). Although the mechanisms by which these mutations affect Aβ are well defined, the precise role PS/γ-secretase on tau pathology in neurodegeneration independently of Aβ is largely unclear. Here we report that neuronal PS deficiency in conditional knockout (cKO) mice results in age-dependent brain atrophy, inflammatory responses and accumulation of pathological tau in neurons and glial cells. Interestingly, genetic inactivation of presenilin 1 (PS1) or both PS genes in mutant human Tau transgenic mice exacerbates memory deficits by accelerating phosphorylation and aggregation of tau in excitatory neurons of vulnerable AD brain regions (e.g., hippocampus, cortex and amygdala). Remarkably, neurofilament (NF) light chain (NF-L) and phosphorylated NF are abnormally accumulated in the brain of Tau mice lacking PS. Synchrotron infrared microspectroscopy revealed aggregated and oligomeric β-sheet structures in amyloid plaque-free PS-deficient Tau mice. Hippocampal-dependent memory deficits are associated with synaptic tau accumulation and reduction of pre- and post-synaptic proteins in Tau mice. Thus, partial loss of PS/γ-secretase in neurons results in temporal- and spatial-dependent tau aggregation associated with memory deficits and neurodegeneration. Our findings show that tau phosphorylation and aggregation are key pathological processes that may underlie neurodegeneration caused by familial AD-linked PSEN mutations. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-021-01259-7.
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spelling pubmed-84825682021-09-30 Loss of presenilin function enhances tau phosphorylation and aggregation in mice Soto-Faguás, Carlos M. Sanchez-Molina, Paula Saura, Carlos A. Acta Neuropathol Commun Research Mutations in the presenilin (PS/PSEN) genes encoding the catalytic components of γ-secretase accelerate amyloid-β (Aβ) and tau pathologies in familial Alzheimer’s disease (AD). Although the mechanisms by which these mutations affect Aβ are well defined, the precise role PS/γ-secretase on tau pathology in neurodegeneration independently of Aβ is largely unclear. Here we report that neuronal PS deficiency in conditional knockout (cKO) mice results in age-dependent brain atrophy, inflammatory responses and accumulation of pathological tau in neurons and glial cells. Interestingly, genetic inactivation of presenilin 1 (PS1) or both PS genes in mutant human Tau transgenic mice exacerbates memory deficits by accelerating phosphorylation and aggregation of tau in excitatory neurons of vulnerable AD brain regions (e.g., hippocampus, cortex and amygdala). Remarkably, neurofilament (NF) light chain (NF-L) and phosphorylated NF are abnormally accumulated in the brain of Tau mice lacking PS. Synchrotron infrared microspectroscopy revealed aggregated and oligomeric β-sheet structures in amyloid plaque-free PS-deficient Tau mice. Hippocampal-dependent memory deficits are associated with synaptic tau accumulation and reduction of pre- and post-synaptic proteins in Tau mice. Thus, partial loss of PS/γ-secretase in neurons results in temporal- and spatial-dependent tau aggregation associated with memory deficits and neurodegeneration. Our findings show that tau phosphorylation and aggregation are key pathological processes that may underlie neurodegeneration caused by familial AD-linked PSEN mutations. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-021-01259-7. BioMed Central 2021-09-30 /pmc/articles/PMC8482568/ /pubmed/34593029 http://dx.doi.org/10.1186/s40478-021-01259-7 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Soto-Faguás, Carlos M.
Sanchez-Molina, Paula
Saura, Carlos A.
Loss of presenilin function enhances tau phosphorylation and aggregation in mice
title Loss of presenilin function enhances tau phosphorylation and aggregation in mice
title_full Loss of presenilin function enhances tau phosphorylation and aggregation in mice
title_fullStr Loss of presenilin function enhances tau phosphorylation and aggregation in mice
title_full_unstemmed Loss of presenilin function enhances tau phosphorylation and aggregation in mice
title_short Loss of presenilin function enhances tau phosphorylation and aggregation in mice
title_sort loss of presenilin function enhances tau phosphorylation and aggregation in mice
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482568/
https://www.ncbi.nlm.nih.gov/pubmed/34593029
http://dx.doi.org/10.1186/s40478-021-01259-7
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