Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer’s Disease: From Early to Advanced Pathological Stages

Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer’s Disease: From Early to Advanced Pathological Stages

In addition to cognitive decline, individuals affected by Alzheimer’s disease (AD) can experience important neuropsychiatric symptoms including sleep disturbances. We characterized the sleep-wake cycle in the TgCRND8 mouse model of AD, which overexpresses a mutant human form of amyloid precursor pro...

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Main Authors: Colby-Milley, Jessica, Cavanagh, Chelsea, Jego, Sonia, Breitner, John C. S., Quirion, Rémi, Adamantidis, Antoine
Format: Online
Language:English
Published: Public Library of Science 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468206/
id pubmed-4468206
recordtype oai_dc
spelling pubmed-44682062015-06-25 Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer’s Disease: From Early to Advanced Pathological Stages Colby-Milley, Jessica Cavanagh, Chelsea Jego, Sonia Breitner, John C. S. Quirion, Rémi Adamantidis, Antoine Research Article In addition to cognitive decline, individuals affected by Alzheimer’s disease (AD) can experience important neuropsychiatric symptoms including sleep disturbances. We characterized the sleep-wake cycle in the TgCRND8 mouse model of AD, which overexpresses a mutant human form of amyloid precursor protein resulting in high levels of β-amyloid and plaque formation by 3 months of age. Polysomnographic recordings in freely-moving mice were conducted to study sleep-wake cycle architecture at 3, 7 and 11 months of age and corresponding levels of β-amyloid in brain regions regulating sleep-wake states were measured. At all ages, TgCRND8 mice showed increased wakefulness and reduced non-rapid eye movement (NREM) sleep during the resting and active phases. Increased wakefulness in TgCRND8 mice was accompanied by a shift in the waking power spectrum towards fast frequency oscillations in the beta (14-20 Hz) and low gamma range (20-50 Hz). Given the phenotype of hyperarousal observed in TgCRND8 mice, the role of noradrenergic transmission in the promotion of arousal, and previous work reporting an early disruption of the noradrenergic system in TgCRND8, we tested the effects of the alpha-1-adrenoreceptor antagonist, prazosin, on sleep-wake patterns in TgCRND8 and non-transgenic (NTg) mice. We found that a lower dose (2 mg/kg) of prazosin increased NREM sleep in NTg but not in TgCRND8 mice, whereas a higher dose (5 mg/kg) increased NREM sleep in both genotypes, suggesting altered sensitivity to noradrenergic blockade in TgCRND8 mice. Collectively our results demonstrate that amyloidosis in TgCRND8 mice is associated with sleep-wake cycle dysfunction, characterized by hyperarousal, validating this model as a tool towards understanding the relationship between β-amyloid overproduction and disrupted sleep-wake patterns in AD. Public Library of Science 2015-06-15 /pmc/articles/PMC4468206/ /pubmed/26076358 http://dx.doi.org/10.1371/journal.pone.0130177 Text en © 2015 Colby-Milley et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Colby-Milley, Jessica
Cavanagh, Chelsea
Jego, Sonia
Breitner, John C. S.
Quirion, Rémi
Adamantidis, Antoine
spellingShingle Colby-Milley, Jessica
Cavanagh, Chelsea
Jego, Sonia
Breitner, John C. S.
Quirion, Rémi
Adamantidis, Antoine
Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer’s Disease: From Early to Advanced Pathological Stages
author_facet Colby-Milley, Jessica
Cavanagh, Chelsea
Jego, Sonia
Breitner, John C. S.
Quirion, Rémi
Adamantidis, Antoine
author_sort Colby-Milley, Jessica
title Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer’s Disease: From Early to Advanced Pathological Stages
title_short Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer’s Disease: From Early to Advanced Pathological Stages
title_full Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer’s Disease: From Early to Advanced Pathological Stages
title_fullStr Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer’s Disease: From Early to Advanced Pathological Stages
title_full_unstemmed Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer’s Disease: From Early to Advanced Pathological Stages
title_sort sleep-wake cycle dysfunction in the tgcrnd8 mouse model of alzheimer’s disease: from early to advanced pathological stages
description In addition to cognitive decline, individuals affected by Alzheimer’s disease (AD) can experience important neuropsychiatric symptoms including sleep disturbances. We characterized the sleep-wake cycle in the TgCRND8 mouse model of AD, which overexpresses a mutant human form of amyloid precursor protein resulting in high levels of β-amyloid and plaque formation by 3 months of age. Polysomnographic recordings in freely-moving mice were conducted to study sleep-wake cycle architecture at 3, 7 and 11 months of age and corresponding levels of β-amyloid in brain regions regulating sleep-wake states were measured. At all ages, TgCRND8 mice showed increased wakefulness and reduced non-rapid eye movement (NREM) sleep during the resting and active phases. Increased wakefulness in TgCRND8 mice was accompanied by a shift in the waking power spectrum towards fast frequency oscillations in the beta (14-20 Hz) and low gamma range (20-50 Hz). Given the phenotype of hyperarousal observed in TgCRND8 mice, the role of noradrenergic transmission in the promotion of arousal, and previous work reporting an early disruption of the noradrenergic system in TgCRND8, we tested the effects of the alpha-1-adrenoreceptor antagonist, prazosin, on sleep-wake patterns in TgCRND8 and non-transgenic (NTg) mice. We found that a lower dose (2 mg/kg) of prazosin increased NREM sleep in NTg but not in TgCRND8 mice, whereas a higher dose (5 mg/kg) increased NREM sleep in both genotypes, suggesting altered sensitivity to noradrenergic blockade in TgCRND8 mice. Collectively our results demonstrate that amyloidosis in TgCRND8 mice is associated with sleep-wake cycle dysfunction, characterized by hyperarousal, validating this model as a tool towards understanding the relationship between β-amyloid overproduction and disrupted sleep-wake patterns in AD.
publisher Public Library of Science
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468206/
_version_ 1613235957400600576

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