Abnormal Clock Gene Expression and Locomotor Activity Rhythms in Two Month-Old Female APPSwe/PS1dE9 Mice

Oyegbami, Olaide; Collins, Hilary M.; Pardon, Marie‐Christine; Ebling, F. J.; Heery, David M.; Moran, Paula M.

doi:10.2174/1567205014666170317113159

Cited by 28 publications

(20 citation statements)

References 56 publications

(76 reference statements)

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“…This study, which examined mice at multiple ages and included a variety of light manipulations and Per2-luciferase rhythm recordings in SCN and various peripheral tissues (such as liver, lung, and spleen), revealed only a minimal delay in activity onset after lights-off in transgenic mice (Kent et al, 2019). Moreover, several studies demonstrate circadian changes which precede amyloid plaque pathology, suggesting possible strain or transgene effects, though an effect of soluble Aβ cannot be excluded (Bedrosian et al, 2011;Ortiz-Tudela et al, 2014;Oyegbami et al, 2017;Ni et al, 2019). While not a true circadian study, Roh et al (2012) demonstrated blunting of amplitude in diurnal rhythms in sleep and brain lactate levels in APPswe/PS1dE9 mice, which was reversible with immunization of an anti-Aβ antibody, suggesting that amyloid pathology may indeed contribute to some aspects of rhythm dysfunction.…”

Section: App and App/ps1 Micementioning

confidence: 88%

“…However, results of circadian studies in APP and APP/PS1 mice do not clearly demonstrate consistent AD-like phenotypes. Several studies have shown increased activity in these mouse lines during the dark phase (the active phase of mice), as well as increases in circadian amplitude (Ambrée et al, 2006;Bedrosian et al, 2011;Baño Otalora et al, 2012;Oyegbami et al, 2017). Aside from this, the wide variety of subtle and oft-conflicting circadian phenotypes in APP and APP/PS1 mouse studies can be appreciated in Table 1.…”

Section: App and App/ps1 Micementioning

confidence: 97%

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Evaluating Circadian Dysfunction in Mouse Models of Alzheimer’s Disease: Where Do We Stand?

Sheehan

Musiek

2020

Front. Neurosci.

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Circadian dysfunction has been described in patients with symptomatic Alzheimer's disease (AD), as well as in presymptomatic phases of the disease. Modeling this circadian dysfunction in mouse models would provide an optimal platform for understanding mechanisms and developing therapies. While numerous studies have examined behavioral circadian function, and in some cases clock gene oscillation, in mouse models of AD, the results are variable and inconsistent across models, ages, and conditions. Ultimately, circadian changes observed in APP/PS1 models are inconsistent across studies and do not always replicate circadian phenotypes observed in human AD. Other models, including the 3xTG mouse, tau transgenic lines, and the accelerated aging SAMP8 line, show circadian phenotypes more consistent with human AD, although the literature is either inconsistent or minimal. We summarize these data and provide some recommendations to improve and standardize future studies of circadian function in AD mouse models.

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Section: App and App/ps1 Micementioning

confidence: 88%

Section: App and App/ps1 Micementioning

confidence: 97%

Evaluating Circadian Dysfunction in Mouse Models of Alzheimer’s Disease: Where Do We Stand?

Sheehan

Musiek

2020

Front. Neurosci.

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“…46 Thus, it is possible that both aging and preclinical AD influence circadian function by causing loss or dysfunction of vasoactive intestinal peptideexpressing neurons in the SCN. Alternative mechanisms of core clock disruption in AD, such as disrupted methylation of the BMAL1 promoter 52 or direct effects of Aβ on clock gene homeostasis, have been suggested 53,54 but, to our knowledge, have not been evaluated in preclinical AD. Disrupted light input to the SCN in AD, owing to loss of melanopsin-containing photoreceptors 55 or inadequate light exposure, 56 have been described in symptomatic AD and could potentially influence our findings, although it is unknown whether these are present in our otherwise healthy preclinical cohort.…”

Section: Discussionmentioning

confidence: 99%

Circadian Rest-Activity Pattern Changes in Aging and Preclinical Alzheimer Disease

et al. 2018

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IMPORTANCE Circadian rhythm disturbances occur in symptomatic Alzheimer disease (AD) and have been hypothesized to contribute to disease pathogenesis. However, it is unknown whether circadian changes occur during the presymptomatic phase of the disease. OBJECTIVE To examine the associations between circadian function, aging, and preclinical AD pathology in cognitively normal adults. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study was conducted using community volunteers from the Knight Alzheimer's Disease Research Center at Washington University in St Louis. Cognitively normal participants (n = 205) underwent 7 to 14 days of actigraphy in their home environment between 2010 and 2012, in addition to clinical assessment, amyloid imaging with Pittsburgh Compound B (PiB), and cerebrospinal fluid biomarker collection. Data collected from 3 years before to 6 months after actigraphy were included. Sixteen participants were excluded owing to incomplete data collection. MAIN OUTCOMES AND MEASURES Circadian rhythm analysis was performed on actigraphy data using 3 methods: cosinor, nonparametric, and empirical mode decomposition. Preclinical AD was assessed by longitudinal clinical assessment, amyloid imaging with PiB, and cerebrospinal fluid biomarker collection. RESULTS Data from 189 participants were included in the analyses. The mean (SD) age was 66.6 (8.3) years, and 121 participants (64%) were women. Older age (β = .247; P = .003) and male sex (β = .170; P = .04), in the absence of amyloid pathology, were associated with a significant increase in intradaily variability, a nonparametric measure of rest-activity rhythm fragmentation, as well as decreased amplitude by several measures. After correction for age and sex, the presence of preclinical amyloid plaque pathology, assessed by positive PiB imaging (mean [SD], 0.804 [0.187] for PiB negative vs 0.875 [0.178] for PiB positive; P = .05) or increasing cerebrospinal fluid phosphorylated-tau to amyloid β 42 ratio (β = .231; P = .008), was associated with increased intradaily variability, indicating rest-activity rhythm fragmentation. CONCLUSIONS AND RELEVANCE Preclinical AD is associated with rest-activity rhythm fragmentation, independent of age or sex. Aging was also associated with circadian dysfunction independently of preclinical AD pathology, particularly in men. The presence of circadian rhythm abnormalities in the preclinical phase of AD suggests that circadian dysfunction could contribute to early disease pathogenesis or serve as a biomarker of preclinical disease.

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“…Circadian abnormalities are observed in transgenic mouse models of AD, including those expressing human mutant amyloid precursor protein (APP), tau, or both. However, there is great heterogeneity across mouse models, and little correlation with pathology, obscuring any definitive mechanistic conclusions (65)(66)(67). Aβ peptide has been implicated as a mediator of circadian dysfunction, and in cultured cells it can induce degradation of the master clock protein BMAL1 (68,69).…”

Section: Underlying Mechanismsmentioning

confidence: 99%

Association between circadian rhythms and neurodegenerative diseases

Leng

Musiek

et al. 2019

The Lancet Neurology

438

386

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Dysfunction in 24-h circadian rhythms is a common occurrence in aging adults, however, circadian rhythm disruptions (CRD) are more severe in people with age-related neurodegenerative diseases, including Alzheimer's disease and related dementias (ADRD) and Parkinson's disease (PD). Manifestations of CRD differ according to type and severity of neurodegenerative disease, and importantly, could occur before onset of typical clinical symptoms of neurodegeneration. Evidence from preliminary studies suggest that-in addition to being a symptom of neurodegeneration-CRD might also be a potential risk factor for developing ADRD and PD, although large, longitudinal studies are needed to confirm this. The mechanistic link between *

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Abnormal Clock Gene Expression and Locomotor Activity Rhythms in Two Month-Old Female APPSwe/PS1dE9 Mice

Cited by 28 publications

References 56 publications

Evaluating Circadian Dysfunction in Mouse Models of Alzheimer’s Disease: Where Do We Stand?

Evaluating Circadian Dysfunction in Mouse Models of Alzheimer’s Disease: Where Do We Stand?

Circadian Rest-Activity Pattern Changes in Aging and Preclinical Alzheimer Disease

Association between circadian rhythms and neurodegenerative diseases

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