RCAN1 Knockout and Overexpression Recapitulate an Ensemble of Rest-activity and Circadian Disruptions Characteristic of Down Syndrome, Alzheimer’s Disease, and Normative Aging

Abstract Background: Regulator of calcineurin 1 (RCAN1) is overexpressed in Down syndrome (DS), but RCAN1 levels are also increased in Alzheimer's disease (AD) and normal aging. AD is highly comorbid among individuals with DS and is characterized in part by progressive neurodegeneration that resembles accelerated aging. Importantly, abnormal RCAN1 levels have been demonstrated to promote memory deficits and pathophysiology symptomatic of DS, AD, and aging. Anomalous diurnal rest-activity patterns and circadian rhythm disruptions are also common in DS, AD, and aging and have been implicated in facilitating age-related cognitive decline and AD progression. However, no prior studies have assessed whether RCAN1 dysregulation may also promote the age-associated alteration of rest-activity profiles and circadian rhythms, which could in turn contribute to neurodegeneration in DS, AD, and aging. Methods: The present study examined the impacts of RCAN1 deficiency and overexpression on the photic entrainment, circadian periodicity, intensity and distribution, diurnal patterning, and circadian rhythmicity of wheel running in young (3-6 months old) and aged (9-14 months old) mice. All data were initially analyzed by multifactorial ANOVA with variables of genotype, age, treatment, and sex considered as dependent variables.Results: We found that daily RCAN1 levels in the hippocampi of light-entrained young mice are generally constant and that balanced RCAN1 expression is necessary for normal circadian locomotor activity rhythms. While the light-entrained diurnal period was unaltered, RCAN1-null and -overexpressing mice displayed lengthened endogenous (free-running) circadian periods like mouse models of AD and aging. In light-entrained young mice, RCAN1 knockout and overexpression also recapitulated the general hypoactivity, diurnal rest-wake pattern fragmentation, and attenuated amplitudes of circadian activity rhythms reported in DS, preclinical and clinical AD, healthily aging individuals, and rodent models thereof. Under constant darkness, RCAN1-null and -overexpressing mice displayed altered locomotor behavior indicating circadian clock dysfunction. Using the Dp(16)1Yey/+ (Dp16) mouse model for DS, which expresses three copies of Rcan1, we found reduced wheel running activity and rhythmicity in both light-entrained and free-running young Dp16 mice like young RCAN1-overexpressing mice. Critically, these diurnal and circadian deficits were rescued in part or entirely by restoring Rcan1 to two copies in Dp16 mice. Conclusions: Collectively, this study's findings suggest that both loss and aberrant gain of RCAN1 precipitate anomalous light-entrained diurnal and circadian activity patterns emblematic of DS, AD, and aging.

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The circadian rest‐activity patterns in mild‐moderate Alzheimer’s disease patients

Alzheimer s & Dementia ◽

10.1002/alz.052917 ◽

2021 ◽

Vol 17 (S5) ◽

Author(s):

Adriano Targa ◽

Ivan David Benitez ◽

Faride Dakterzada ◽

John Fontenele Araujo ◽

Olga Minguez ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Activity Patterns ◽

Rest Activity

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Sleep and diurnal rest-activity rhythm disturbances in a mouse model of Alzheimer’s disease

SLEEP ◽

10.1093/sleep/zsaa087 ◽

2020 ◽

Vol 43 (11) ◽

Cited By ~ 2

Author(s):

Mikolaj J Filon ◽

Eli Wallace ◽

Samantha Wright ◽

Dylan J Douglas ◽

Lauren I Steinberg ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Eye Movement ◽

Rem Sleep ◽

Activity Levels ◽

Rapid Eye Movement ◽

Drug Bioavailability ◽

Activity Rhythms ◽

Delta Power ◽

Rest Activity

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Comparative locomotor activity patterns in the portunid crabs Liocarcinus holsatus and L. depurator

Journal of the Marine Biological Association of the United Kingdom ◽

10.1017/s0025315400037346 ◽

1991 ◽

Vol 71 (1) ◽

pp. 1-10 ◽

Cited By ~ 22

Author(s):

P. Abelló ◽

D. G. Reid ◽

E. Naylor

Keyword(s):

Locomotor Activity ◽

Activity Patterns ◽

High Tide ◽

Sandy Beaches ◽

Maximum Activity ◽

Circadian Activity ◽

Activity Rhythms ◽

Sublittoral Zone ◽

Free Running ◽

Behavioural Mechanism

The free-running locomotor activity rhythms of freshly-captured swimming crabs Liocarcinus holsatus and L. depurator have been studied in constant conditions in the laboratory. L. holsatus captured in the intertidal zone of sandy beaches showed strong circatidal activity rhythms with maximum activity at high tide. L. holsatus captured in the sublittoral zone had a clear tendency to show circadian activity rhythms with highest activity during day-time hours. L. depurator occurred only sublittorally and showed circadian activity patterns with highest activity during the night. Exposure to hydrostatic pressure cycles of tidal amplitude and periodicity, entrained strong circatidal activity rhythms in previously arhythmic L. holsatus. This activity pattern also showed a marked circadian component. Exposure to the same regime entrained a circadian rhythm, but not a circatidal rhythm in L. depurator. In the sublittoral zone L. depurator is active mainly during the night, whereas L. holsatus, is active mainly during the day. This may constitute a behavioural mechanism for minimizing competitive interactions between these two sympatric crabs.

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Actigraphic monitoring of movement and rest-activity rhythms in aging, Alzheimer's disease and Parkinson's disease

Proceedings of 18th Annual International Conference of the IEEE Engineering in Medicine and Biology Society ◽

10.1109/iembs.1996.656850 ◽

2002 ◽

Cited By ~ 4

Author(s):

E.J.W. van Someren

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Activity Rhythms ◽

Rest Activity

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Actigraphic monitoring of movement and rest-activity rhythms in aging, Alzheimer's disease, and Parkinson's disease

IEEE Transactions on Rehabilitation Engineering ◽

10.1109/86.650297 ◽

1997 ◽

Vol 5 (4) ◽

pp. 394-398 ◽

Cited By ~ 38

Author(s):

E.J.W. Van Someren

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Activity Rhythms ◽

Rest Activity

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045 Associations of Actigraphic Sleep and Circadian Rest/Activity Rhythms with Cognition in the Early Phase of Alzheimer’s Disease

SLEEP ◽

10.1093/sleep/zsab072.044 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A19-A20

Author(s):

Alfonso Alfini ◽

Marilyn Albert ◽

Andreia Faria ◽

Anja Soldan ◽

Corinne Pettigrew ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Executive Function ◽

Episodic Memory ◽

Cognitive Performance ◽

Cognitive Test ◽

Activity Rhythms ◽

Combining Data ◽

Normal Cognition ◽

Rest Activity

Abstract Introduction Alterations in sleep and circadian rhythms are common in persons with Alzheimer’s disease (AD) dementia, but the nature of such changes in the early phases of AD remains unclear. This study compared sleep and circadian rest/activity rhythms (RARs), measured by standard and novel actigraphic indices, between participants with normal cognition or mild cognitive impairment (MCI), and examined cross-sectional associations between these measures and cognition. Methods Actigraphy data were collected in 179 individuals (mean age=72.6 years, gender=64.8% female) with normal cognition (n=153) or MCI (n=26) from the Biomarkers for Older Controls at Risk of Dementia (BIOCARD) study. Standard sleep parameters (i.e., total sleep time [TST], sleep efficiency [SE], wake after sleep onset [WASO], average wake bout length [WBL]), and standard non-parametric RAR metrics (i.e., relative amplitude [RA], intradaily variability [IV], interdaily stability [IS]) were generated. Functional principal component (fPC) methods were used to generate three novel RAR indices (fPC1, fPC2, fPC3) representing 69% of the total variance. Cognitive test scores were used to generate composite measures reflecting the domains of episodic memory and executive function using factor analysis. Regression models were used to compare sleep and circadian RAR parameters between the diagnostic groups and to evaluate their associations with cognitive performance. Results After adjustment for age, sex, education, and APOE-4 genotype, compared to normal controls, MCI subjects had significantly lower SE, lower RA, and lower scores on the novel RAR measure fPC3, which reflects a later rhythm phase, lower amplitude, and lower activity both at night and early in the day. In analyses combining data from participants with MCI and controls, several standard RAR parameters (e.g., higher RA and IS) and higher fPC3 scores were associated with both better episodic memory and executive function. Additionally, several standard measures (e.g., lower WASO and IV) and lower fPC1 scores (reflecting higher rhythm amplitude and greater activity throughout daytime hours) were linked with better executive function. Conclusion MCI participants have sleep and circadian alterations, which are significantly associated with cognitive performance. A novel RAR measure, fPC3, showed differences in rhythm patterns that extended from the night into the daytime. Support (if any) Funding-support NIA (U19-AG033655, T32-AG027668, R01-AG050507) and AASMF (#223-BS-19).

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Differential associations of age and Alzheimer's disease with sleep and rest-activity rhythms across the adult lifespan

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2021.01.006 ◽

2021 ◽

Vol 101 ◽

pp. 141-149

Author(s):

Jee Eun Park ◽

Yu Jin Lee ◽

Min Soo Byun ◽

Dahyun Yi ◽

Jun Ho Lee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Activity Rhythms ◽

Adult Lifespan ◽

Rest Activity

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Sleep and Diurnal Rest-Activity Rhythm Disturbances in a Mouse Model of Alzheimer’s Disease

10.1101/2020.02.17.950600 ◽

2020 ◽

Cited By ~ 1

Author(s):

Mikolaj J. Filon ◽

Eli Wallace ◽

Samantha Wright ◽

Dylan J. Douglas ◽

Lauren I. Steinberg ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rem Sleep ◽

Activity Rhythm ◽

Activity Levels ◽

Wild Type ◽

Drug Bioavailability ◽

Activity Rhythms ◽

Delta Power ◽

Rest Activity

AbstractStudy ObjectivesAccumulating evidence suggests a strong association between sleep, amyloid-beta (Aβ) deposition, and Alzheimer’s disease (AD). We sought to determine if: (1) deficits in rest-activity rhythms and sleep are significant phenotypes in J20 AD mice, (2) metabotropic glutamate receptor 5 inhibitors (mGluR5) could rescue deficits in rest-activity rhythms and sleep, and (3) Aβ levels are responsive to treatment with mGluR5 inhibitors.MethodsDiurnal rest-activity levels were measured by actigraphy and sleep-wake patterns by electroencephalography (EEG), while animals were chronically treated with mGluR5 inhibitors. Behavioral tests were performed, and Aβ levels measured in brain lysates.ResultsJ20 mice exhibited a 4.5 hour delay in the acrophase of activity levels compared to wild-type littermates, and spent less time in REM sleep during the second half of the light period. J20 mice also exhibited decreased NREM delta power but increased NREM sigma power. The mGluR5 inhibitor CTEP rescued the REM sleep deficit and improved NREM delta and sigma power but did not correct rest-activity rhythms. No statistically significant differences were observed in Aβ levels, rotarod performance or the passive avoidance task following chronic mGluR5 inhibitor treatment.ConclusionsJ20 mice have disruptions in rest-activity rhythms and reduced homeostatic sleep pressure (reduced NREM delta power). NREM delta power was increased following treatment with an mGluR5 inhibitor. Drug bioavailability was poor. Further work is necessary to determine if mGluR5 is a viable target for treating sleep phenotypes in AD.Statement of SignificanceSleep disruption is evolving as an important risk factor as well as phenotype of neurological diseases including Alzheimer’s disease. This study is novel in determining alterations in the rest-activity rhythm and sleep-wake pattern of J20 Alzheimer’s disease mice and wild type littermates. Specifically, there is a delay in acrophase with prolonged hyperactivity during the dark cycle, and reduced sleep pressure that was improved by treatment with mGluR5 inhibitor. Critical remaining knowledge gaps and future directions include testing the effects of Alzheimer’s disease drugs on rescue of sleep and rest-activity patterns in other Alzheimer’s disease models. These studies are relevant to human Alzheimer’s disease as monitoring sleep phenotypes may predict disease risk, and therapies that normalize sleep patterns may slow progression.

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