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Neurons in Vulnerable Regions of the Alzheimer’s Disease Brain Display Reduced ATM Signaling123

Ataxia telangiectasia (A-T) is a multisystemic disease caused by mutations in the ATM (A-T mutated) gene. It strikes before 5 years of age and leads to dysfunctions in many tissues, including the CNS, where it leads to neurodegeneration, primarily in cerebellum. Alzheimer’s disease (AD), by contrast...

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Detalles Bibliográficos
Autores principales: Shen, Xuting, Chen, Jianmin, Li, Jiali, Kofler, Julia, Herrup, Karl
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770009/
https://www.ncbi.nlm.nih.gov/pubmed/27022623
http://dx.doi.org/10.1523/ENEURO.0124-15.2016
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author Shen, Xuting
Chen, Jianmin
Li, Jiali
Kofler, Julia
Herrup, Karl
author_facet Shen, Xuting
Chen, Jianmin
Li, Jiali
Kofler, Julia
Herrup, Karl
author_sort Shen, Xuting
collection PubMed
description Ataxia telangiectasia (A-T) is a multisystemic disease caused by mutations in the ATM (A-T mutated) gene. It strikes before 5 years of age and leads to dysfunctions in many tissues, including the CNS, where it leads to neurodegeneration, primarily in cerebellum. Alzheimer’s disease (AD), by contrast, is a largely sporadic neurodegenerative disorder that rarely strikes before the 7th decade of life with primary neuronal losses in hippocampus, frontal cortex, and certain subcortical nuclei. Despite these differences, we present data supporting the hypothesis that a failure of ATM signaling is involved in the neuronal death in individuals with AD. In both, partially ATM-deficient mice and AD mouse models, neurons show evidence for a loss of ATM. In human AD, three independent indices of reduced ATM function—nuclear translocation of histone deacetylase 4, trimethylation of histone H3, and the presence of cell cycle activity—appear coordinately in neurons in regions where degeneration is prevalent. These same neurons also show reduced ATM protein levels. And though they represent only a fraction of the total neurons in each affected region, their numbers significantly correlate with disease stage. This previously unknown role for the ATM kinase in AD pathogenesis suggests that the failure of ATM function may be an important contributor to the death of neurons in AD individuals.
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spelling pubmed-47700092016-03-28 Neurons in Vulnerable Regions of the Alzheimer’s Disease Brain Display Reduced ATM Signaling123 Shen, Xuting Chen, Jianmin Li, Jiali Kofler, Julia Herrup, Karl eNeuro New Research Ataxia telangiectasia (A-T) is a multisystemic disease caused by mutations in the ATM (A-T mutated) gene. It strikes before 5 years of age and leads to dysfunctions in many tissues, including the CNS, where it leads to neurodegeneration, primarily in cerebellum. Alzheimer’s disease (AD), by contrast, is a largely sporadic neurodegenerative disorder that rarely strikes before the 7th decade of life with primary neuronal losses in hippocampus, frontal cortex, and certain subcortical nuclei. Despite these differences, we present data supporting the hypothesis that a failure of ATM signaling is involved in the neuronal death in individuals with AD. In both, partially ATM-deficient mice and AD mouse models, neurons show evidence for a loss of ATM. In human AD, three independent indices of reduced ATM function—nuclear translocation of histone deacetylase 4, trimethylation of histone H3, and the presence of cell cycle activity—appear coordinately in neurons in regions where degeneration is prevalent. These same neurons also show reduced ATM protein levels. And though they represent only a fraction of the total neurons in each affected region, their numbers significantly correlate with disease stage. This previously unknown role for the ATM kinase in AD pathogenesis suggests that the failure of ATM function may be an important contributor to the death of neurons in AD individuals. Society for Neuroscience 2016-02-27 /pmc/articles/PMC4770009/ /pubmed/27022623 http://dx.doi.org/10.1523/ENEURO.0124-15.2016 Text en Copyright © 2016 Shen et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle New Research
Shen, Xuting
Chen, Jianmin
Li, Jiali
Kofler, Julia
Herrup, Karl
Neurons in Vulnerable Regions of the Alzheimer’s Disease Brain Display Reduced ATM Signaling123
title Neurons in Vulnerable Regions of the Alzheimer’s Disease Brain Display Reduced ATM Signaling123
title_full Neurons in Vulnerable Regions of the Alzheimer’s Disease Brain Display Reduced ATM Signaling123
title_fullStr Neurons in Vulnerable Regions of the Alzheimer’s Disease Brain Display Reduced ATM Signaling123
title_full_unstemmed Neurons in Vulnerable Regions of the Alzheimer’s Disease Brain Display Reduced ATM Signaling123
title_short Neurons in Vulnerable Regions of the Alzheimer’s Disease Brain Display Reduced ATM Signaling123
title_sort neurons in vulnerable regions of the alzheimer’s disease brain display reduced atm signaling123
topic New Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770009/
https://www.ncbi.nlm.nih.gov/pubmed/27022623
http://dx.doi.org/10.1523/ENEURO.0124-15.2016
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