Circadian disruption has long been recognized as a symptom of Alzheimer’s disease (AD); however, emerging data suggests that circadian dysfunction occurs early on in disease development, potentially preceding any noticeable cognitive deficits.
Objective:
This study compares the onset of AD in male and female wild type (C57BL6/J), transgenic (AβPP/PS1), and knock-in (APPNL-F/NL-F) AD mouse models from the period of plaque initiation (6 months) through 12 months.
Methods:
Rhythmic daily activity patterns, glucose sensitivity, cognitive function (Morris water maze, MWM), and AD pathology (plaques formation) were assessed. A comparison was made across sexes.
Results:
Sex-dependent hyperactivity in AβPP/PS1 mice was observed. In comparison to C57BL/6J animals, 6-month-old male AβPP/PS1 demonstrated nighttime hyperactivity, as did 12-month-old females. Female AβPP/PS1 animals performed significantly worse on a MWM task than AβPP/PS1 males at 12 months and trended toward increased plaque pathology. APPNL-F/NL-F 12-month-old males performed significantly worse on the MWM task compared to 12-month-old females. Significantly greater plaque pathology occurred in AβPP/PS1 animals as compared to APPNL-F/NL-F animals. Female AβPP/PS1 animals performed significantly worse than APPNL-F/NL-F animals in spatial learning and memory tasks, though this was reversed in males.
Conclusion:
Taken together, this study provides novel insights into baseline sex differences, as well as characterizes baseline diurnal activity variations, in the AβPP/PS1 and APPNL-F/NL-F AD mouse models.
JackCRJr., KnopmanDS, JagustWJ, PetersenRC, WeinerMW, AisenPS, ShawLM, VemuriP, WisteHJ, WeigandSD, LesnickTG, PankratzVS, DonohueMC, TrojanowskiJQ (2013) Tracking pathophysiological processes in Alzheimer’s disease: An updated hypothetical model of dynamic biomarkers. Lancet Neurol12, 207–216.
2.
SelkoeDJ (2004) Cell biology of protein misfolding: The examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol6, 1054–1061.
3.
Peter-DerexL, YammineP, BastujiH, CroisileB (2015) Sleep and Alzheimer’s disease. Sleep Med Rev19, 29–38.
4.
HatfieldCF, HerbertJ, van SomerenEJ, HodgesJR, HastingsMH (2004) Disrupted daily activity/rest cycles in relation to daily cortisol rhythms of home-dwelling patients with early Alzheimer’s dementia. Brain127, 1061–1074.
5.
HahnEA, WangHX, AndelR, FratiglioniL (2014) A change in sleep pattern may predict Alzheimer disease. Am J Geriatr Psychiatry22, 1262–1271.
6.
DeCourseyPJ, BuggyJ (1989) Circadian rhythmicity after neural transplant to hamster third ventricle: Specificity of suprachiasmatic nuclei. Brain Res500, 263–275.
7.
AbrahamsonEE, MooreRY (2001) Suprachiasmatic nucleus in the mouse: Retinal innervation, intrinsic organization and efferent projections. Brain Res916, 172–191.
MaywoodES, ReddyAB, WongGK, O’NeillJS, O’BrienJA, McMahonDG, HarmarAJ, OkamuraH, HastingsMH (2006) Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling. Curr Biol16, 599–605.
10.
YamaguchiS, IsejimaH, MatsuoT, OkuraR, YagitaK, KobayashiM, OkamuraH (2003) Synchronization of cellular clocks in the suprachiasmatic nucleus. Science302, 1408–1412.
11.
HarmarAJ, MarstonHM, ShenS, SprattC, WestKM, ShewardWJ, MorrisonCF, DorinJR, PigginsHD, ReubiJC, KellyJS, MaywoodES, HastingsMH (2002) The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell109, 497–508.
12.
MiedaM (2019) The network mechanism of the central circadian pacemaker of the SCN: Do AVP neurons play a more critical role than expected?Front Neurosci13, 139.
13.
StephanFK, ZuckerI (1972) Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci U S A69, 1583–1586.
14.
SawakiY, NihonmatsuI, KawamuraH (1984) Transplantation of the neonatal suprachiasmatic nuclei into rats with complete bilateral suprachiasmatic lesions. Neurosci Res1, 67–72.
15.
GolombekDA, RosensteinRE (2010) Physiology of circadian entrainment. Physiol Rev90, 1063–1102.
16.
StopaEG, VolicerL, Kuo-LeblancV, HarperD, LathiD, TateB, SatlinA (1999) Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia. J Neuropathol Exp Neurol58, 29–39.
17.
LiuRY, ZhouJN, HoogendijkWJ, van HeerikhuizeJ, KamphorstW, UnmehopaUA, HofmanMA, SwaabDF (2000) Decreased vasopressin gene expression in the biological clock of Alzheimer disease patients with and without depression. J Neuropathol Exp Neurol59, 314–322.
18.
ZhouJN, HofmanMA, SwaabDF (1995) VIP neurons in the human SCN in relation to sex, age, and Alzheimer’s disease. Neurobiol Aging16, 571–576.
19.
KangJE, LimMM, BatemanRJ, LeeJJ, SmythLP, CirritoJR, FujikiN, NishinoS, HoltzmanDM (2009) Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science326, 1005–1007.
20.
RohJH, HuangY, BeroAW, KastenT, StewartFR, BatemanRJ, HoltzmanDM (2012) Disruption of the sleep-wake cycle and diurnal fluctuation of beta-amyloid in mice with Alzheimer’s disease pathology. Sci Transl Med4, 150ra122.
YanP, BeroAW, CirritoJR, XiaoQ, HuX, WangY, GonzalesE, HoltzmanDM, LeeJM (2009) Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice. J Neurosci29, 10706–10714.
24.
LeeJE, HanPL (2013) An update of animal models of Alzheimer disease with a reevaluation of plaque depositions. Exp Neurobiol22, 84–95.
25.
MasudaA, KobayashiY, KogoN, SaitoT, SaidoTC, ItoharaS (2016) Cognitive deficits in single App knock-in mouse models. Neurobiol Learn Mem135, 73–82.
26.
HallAM, RobersonED (2012) Mouse models of Alzheimer’s disease. Brain Res Bull88, 3–12.
27.
RogersJ, ChurilovL, HannanAJ, RenoirT (2017) Search strategy selection in the Morris water maze indicates allocentric map formation during learning that underpins spatial memory formation. Neurobiol Learn Mem139, 37–49.
28.
GomezG, Beason-HeldLL, BilgelM, AnY, WongDF, StudenskiS, FerrucciL, ResnickSM (2018) Metabolic syndrome and amyloid accumulation in the aging brain. J Alzheimers Dis65, 629–639.
29.
KarakelidesH, IrvingBA, ShortKR, O’BrienP, NairKS (2010) Age, obesity, and sex effects on insulin sensitivity and skeletal muscle mitochondrial function. Diabetes59, 89–97.
30.
JansonJ, LaedtkeT, ParisiJE, O’BrienP, PetersenRC, ButlerPC (2004) Increased risk of type 2 diabetes in Alzheimer disease. Diabetes53, 474–481.
31.
HascupER, BroderickSO, RussellMK, FangY, BartkeA, BogerHA, HascupKN (2019) Diet-induced insulin resistance elevates hippocampal glutamate as well as VGLUT1 and GFAP expression in AbetaPP/PS1 mice. J Neurochem148, 219–237.
32.
Ordonez-GutierrezL, Fernandez-PerezI, HerreraJL, AntonM, Benito-CuestaI, WandosellF (2016) AbetaPP/PS1 transgenic mice show sex differences in the cerebellum associated with aging. J Alzheimers Dis54, 645–656.
33.
HascupKN, FindleyCA, SimeLN, HascupER (2020) Hippocampal alterations in glutamatergic signaling during amyloid progression in AbetaPP/PS1 mice. Sci Rep10, 14503.
34.
SchonheitB, ZarskiR, OhmTG (2004) Spatial and temporal relationships between plaques and tangles in Alzheimer-pathology. Neurobiol Aging25, 697–711.
35.
ZhaoJ, O’ConnorT, VassarR (2011) The contribution of activated astrocytes to Abeta production: Implications for Alzheimer’s disease pathogenesis. J Neuroinflammation8, 150.
36.
AbdulHM, SamaMA, FurmanJL, MathisDM, BeckettTL, WeidnerAM, PatelES, BaigI, MurphyMP, LeVineH, 3rd, KranerSD, NorrisCM (2009) Cognitive decline in Alzheimer’s disease is associated with selective changes in calcineurin/NFAT signaling. J Neurosci29, 12957–12969.
37.
HascupKN, FindleyCA, BritzJ, Esperant-HilaireN, BroderickSO, DelfinoK, TischkauS, BartkeA, HascupER (2021) Riluzole attenuates glutamatergic tone and cognitive decline in AbetaPP/PS1 mice. J Neurochem156, 513–523.
38.
ThalDR, SchultzC, DehghaniF, YamaguchiH, BraakH, BraakE (2000) Amyloid beta-protein (Abeta)-containing astrocytes are located preferentially near N-terminal-truncated Abeta deposits in the human entorhinal cortex. Acta Neuropathol100, 608–617.
39.
Perez-NievasBG, Serrano-PozoA (2018) Deciphering the astrocyte reaction in Alzheimer’s disease. Front Aging Neurosci10, 114.
40.
KatsouriL, BirchAM, RenziehausenAWJ, ZachC, AmanY, SteedsH, BonsuA, PalmerEOC, MirzaeiN, RiesM, SastreM (2020) Ablation of reactive astrocytes exacerbates disease pathology in a model of Alzheimer’s disease. Glia68, 1017–1030.
41.
TsoCF, SimonT, GreenlawAC, PuriT, MiedaM, HerzogED (2017) Astrocytes regulate daily rhythms in the suprachiasmatic nucleus and behavior. Curr Biol27, 1055–1061.
42.
LanannaBV, McKeeCA, KingMW, Del-AguilaJL, DimitryJM, FariasFHG, NadarajahCJ, XiongDD, GuoC, CammackAJ, EliasJA, ZhangJ, CruchagaC, MusiekES (2020) Chi3l1/YKL-40 is controlled by the astrocyte circadian clock and regulates neuroinflammation and Alzheimer’s disease pathogenesis. , eaax. Sci Transl Med12, 3519.
43.
McCauleyJP, PetroccioneMA, D’BrantLY, ToddGC, AffinnihN, WisnoskiJJ, ZahidS, ShreeS, SousaAA, De GuzmanRM, MiglioreR, BrazheA, LeapmanRD, KhmaladzeA, SemyanovA, ZuloagaDG, MiglioreM, ScimemiA (2020) Circadian modulation of neurons and astrocytes controls synaptic plasticity in hippocampal area CA1. Cell Rep33, 108255.
44.
NakamuraTJ, TakasuNN, NakamuraW (2016) The suprachiasmatic nucleus: Age-related decline in biological rhythms. J Physiol Sci66, 367–374.
FarajniaS, DeboerT, RohlingJH, MeijerJH, MichelS (2014) Aging of the suprachiasmatic clock. Neuroscientist20, 44–55.
47.
JonesJR, SimonT, LonesL, HerzogED (2018) SCN VIP neurons are essential for normal light-mediated resetting of the circadian system. J Neurosci38, 7986–7995.
48.
MazuskiC, AbelJH, ChenSP, HermanstyneTO, JonesJR, SimonT, DoyleFJ, 3rd, HerzogED (2018) Entrainment of circadian rhythms depends on firing rates and neuropeptide release of VIP SCN neurons. Neuron99, 555–563e555.
49.
SterniczukR, AntleMC, LaferlaFM, DyckRH (2010) Characterization of the 3xTg-AD mouse model of Alzheimer’s disease: Part 2. Behavioral and cognitive changes. Brain Res1348, 149–155.
50.
MaZ, JiangW, ZhangEE (2016) Orexin signaling regulates both the hippocampal clock and the circadian oscillation of Alzheimer’s disease-risk genes. Sci Rep6, 36035.
51.
VolianskisA, KostnerR, MolgaardM, HassS, JensenMS (2010) Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe/PS1deltaE9-deleted transgenic mice model of ss-amyloidosis. Neurobiol Aging31, 1173–1187.
52.
Diaz BrintonR (2012) Minireview: Translational animal models of human menopause: Challenges and emerging opportunities. Endocrinology153, 3571–3578.
53.
Mauvais-JarvisF (2018) Gender differences in glucose homeostasis and diabetes. Physiol Behav187, 20–23.
54.
SharmaG, Mauvais-JarvisF, ProssnitzER (2018) Roles of Gprotein-coupled estrogen receptor GPER in metabolic regulation. J Steroid Biochem Mol Biol176, 31–37.
55.
HoyerS (2002) The brain insulin signal transduction system andsporadic (type II) Alzheimer disease: An update. J NeuralTransm (Vienna)109, 341–360.
