Cargando…

Chronic Sleep Disruption Advances the Temporal Progression of Tauopathy in P301S Mutant Mice

Brainstem locus ceruleus neurons (LCn) are among the first neurons across the lifespan to evidence tau pathology, and LCn are implicated in tau propagation throughout the cortices. Yet, events influencing LCn tau are poorly understood. Activated persistently across wakefulness, LCn experience signif...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhu, Yan, Zhan, Guanxia, Fenik, Polina, Brandes, Madison, Bell, Patrick, Francois, Noelle, Shulman, Katherine, Veasey, Sigrid
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262148/
https://www.ncbi.nlm.nih.gov/pubmed/30322903
http://dx.doi.org/10.1523/JNEUROSCI.0275-18.2018
_version_ 1783375047326433280
author Zhu, Yan
Zhan, Guanxia
Fenik, Polina
Brandes, Madison
Bell, Patrick
Francois, Noelle
Shulman, Katherine
Veasey, Sigrid
author_facet Zhu, Yan
Zhan, Guanxia
Fenik, Polina
Brandes, Madison
Bell, Patrick
Francois, Noelle
Shulman, Katherine
Veasey, Sigrid
author_sort Zhu, Yan
collection PubMed
description Brainstem locus ceruleus neurons (LCn) are among the first neurons across the lifespan to evidence tau pathology, and LCn are implicated in tau propagation throughout the cortices. Yet, events influencing LCn tau are poorly understood. Activated persistently across wakefulness, LCn experience significant metabolic stress in response to chronic short sleep (CSS). Here we explored whether CSS influences LCn tau and the biochemical, neuroanatomical, and/or behavioral progression of tauopathy in male and female P301S mice. CSS in early adult life advanced the temporal progression of neurobehavioral impairments and resulted in a lasting increase in soluble tau oligomers. Intriguingly, CSS resulted in an early increase in AT8 and MC1 tau pathology in the LC. Over time tau pathology, including tangles, was evident in forebrain tau-vulnerable regions. Sustained microglial and astrocytic activation was observed as well. Remarkably, CSS resulted in significant loss of neurons in the two regions examined: the basolateral amygdala and LC. A second, distinct form of chronic sleep disruption, fragmentation of sleep, during early adult life also increased tau deposition and imparted early neurobehavioral impairment. Collectively, the findings demonstrate that early life sleep disruption has important lasting effects on the temporal progression in P301S mice, influencing tau pathology and hastening neurodegeneration, neuroinflammation, and neurobehavioral impairments. SIGNIFICANCE STATEMENT Chronic short sleep (CSS) is pervasive in modern society. Here, we found that early life CSS influences behavioral, biochemical, and neuroanatomic aspects of the temporal progression of tauopathy in a mouse model of the P301S tau mutation. Specifically, CSS hastened the onset of motor impairment and resulted in a greater loss of neurons in both the locus ceruleus and basolateral/lateral amygdala. Importantly, despite a protracted recovery opportunity after CSS, mice evidenced a sustained increase in pathogenic tau oligomers, and increased pathogenic tau in the locus ceruleus and limbic system nuclei. These findings unveil early life sleep habits as an important determinant in the progression of tauopathy.
format Online
Article
Text
id pubmed-6262148
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Society for Neuroscience
record_format MEDLINE/PubMed
spelling pubmed-62621482018-12-04 Chronic Sleep Disruption Advances the Temporal Progression of Tauopathy in P301S Mutant Mice Zhu, Yan Zhan, Guanxia Fenik, Polina Brandes, Madison Bell, Patrick Francois, Noelle Shulman, Katherine Veasey, Sigrid J Neurosci Research Articles Brainstem locus ceruleus neurons (LCn) are among the first neurons across the lifespan to evidence tau pathology, and LCn are implicated in tau propagation throughout the cortices. Yet, events influencing LCn tau are poorly understood. Activated persistently across wakefulness, LCn experience significant metabolic stress in response to chronic short sleep (CSS). Here we explored whether CSS influences LCn tau and the biochemical, neuroanatomical, and/or behavioral progression of tauopathy in male and female P301S mice. CSS in early adult life advanced the temporal progression of neurobehavioral impairments and resulted in a lasting increase in soluble tau oligomers. Intriguingly, CSS resulted in an early increase in AT8 and MC1 tau pathology in the LC. Over time tau pathology, including tangles, was evident in forebrain tau-vulnerable regions. Sustained microglial and astrocytic activation was observed as well. Remarkably, CSS resulted in significant loss of neurons in the two regions examined: the basolateral amygdala and LC. A second, distinct form of chronic sleep disruption, fragmentation of sleep, during early adult life also increased tau deposition and imparted early neurobehavioral impairment. Collectively, the findings demonstrate that early life sleep disruption has important lasting effects on the temporal progression in P301S mice, influencing tau pathology and hastening neurodegeneration, neuroinflammation, and neurobehavioral impairments. SIGNIFICANCE STATEMENT Chronic short sleep (CSS) is pervasive in modern society. Here, we found that early life CSS influences behavioral, biochemical, and neuroanatomic aspects of the temporal progression of tauopathy in a mouse model of the P301S tau mutation. Specifically, CSS hastened the onset of motor impairment and resulted in a greater loss of neurons in both the locus ceruleus and basolateral/lateral amygdala. Importantly, despite a protracted recovery opportunity after CSS, mice evidenced a sustained increase in pathogenic tau oligomers, and increased pathogenic tau in the locus ceruleus and limbic system nuclei. These findings unveil early life sleep habits as an important determinant in the progression of tauopathy. Society for Neuroscience 2018-11-28 /pmc/articles/PMC6262148/ /pubmed/30322903 http://dx.doi.org/10.1523/JNEUROSCI.0275-18.2018 Text en Copyright © 2018 Zhu et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License Creative Commons Attribution 4.0 International (https://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 Research Articles
Zhu, Yan
Zhan, Guanxia
Fenik, Polina
Brandes, Madison
Bell, Patrick
Francois, Noelle
Shulman, Katherine
Veasey, Sigrid
Chronic Sleep Disruption Advances the Temporal Progression of Tauopathy in P301S Mutant Mice
title Chronic Sleep Disruption Advances the Temporal Progression of Tauopathy in P301S Mutant Mice
title_full Chronic Sleep Disruption Advances the Temporal Progression of Tauopathy in P301S Mutant Mice
title_fullStr Chronic Sleep Disruption Advances the Temporal Progression of Tauopathy in P301S Mutant Mice
title_full_unstemmed Chronic Sleep Disruption Advances the Temporal Progression of Tauopathy in P301S Mutant Mice
title_short Chronic Sleep Disruption Advances the Temporal Progression of Tauopathy in P301S Mutant Mice
title_sort chronic sleep disruption advances the temporal progression of tauopathy in p301s mutant mice
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262148/
https://www.ncbi.nlm.nih.gov/pubmed/30322903
http://dx.doi.org/10.1523/JNEUROSCI.0275-18.2018
work_keys_str_mv AT zhuyan chronicsleepdisruptionadvancesthetemporalprogressionoftauopathyinp301smutantmice
AT zhanguanxia chronicsleepdisruptionadvancesthetemporalprogressionoftauopathyinp301smutantmice
AT fenikpolina chronicsleepdisruptionadvancesthetemporalprogressionoftauopathyinp301smutantmice
AT brandesmadison chronicsleepdisruptionadvancesthetemporalprogressionoftauopathyinp301smutantmice
AT bellpatrick chronicsleepdisruptionadvancesthetemporalprogressionoftauopathyinp301smutantmice
AT francoisnoelle chronicsleepdisruptionadvancesthetemporalprogressionoftauopathyinp301smutantmice
AT shulmankatherine chronicsleepdisruptionadvancesthetemporalprogressionoftauopathyinp301smutantmice
AT veaseysigrid chronicsleepdisruptionadvancesthetemporalprogressionoftauopathyinp301smutantmice