Central and peripheral circadian clocks and their role in Alzheimer's disease

“Similar changes in the human brain during sleep would favour the bulk flow of CSF and ISF through the perivascular (Rennels et al., 1985) and glymphatic drainage channels (Iliff et al., 2012; Kress et al., 2015; TarasoffConway et al., 2015).”

“Genetic linkage studies in familial AD (Goate et al., 1991; Rogaev et al., 1995; Sherrington et al., 1995) and wholegenome studies of the more common, sporadic form of AD (Jonsson et al.”

“…1995; Sherrington et al., 1995) and wholegenome studies of the more common, sporadic form of AD (Jonsson et al., 2012) indicate that the increased production of aggregationprone Aβ peptides, the main component of plaques (Glenner and Wong, 1984; Masters et al., 1985a,b), might initiate the disease.”

“In addition, genome-wide association studies have implicated a wider range of biological functions that likely contribute to risk of AD, in particular innate immunity and inflammation (Cuyvers and Sleegers, 2016; Guerreiro et al., 2013; Jonsson et al., 2013; Lambert et al., 2013; Singleton and Hardy, 2016).”

“APP (the so-called Swedish mutation), PSEN1 and tau (Oddo et al., 2003).”

“Genetic linkage studies in familial AD (Goate et al., 1991; Rogaev et al., 1995; Sherrington et al., 1995) and wholegenome studies of the more common, sporadic form of AD (Jonsson et al.”

“Circadian oscillations in the levels of Aβ are mirrored by orexin, a hormone released from neurones in the hypothalamus (de Lecea et al., 1998).”

“Orexin knockout mice sleep more than controls (Chemelli et al., 1999), and when crossed with APP/ PSEN1 mice, they exhibit a marked reduction in Aβ plaque deposition (Roh et al., 2014).”

“In addition, genome-wide association studies have implicated a wider range of biological functions that likely contribute to risk of AD, in particular innate immunity and inflammation (Cuyvers and Sleegers, 2016; Guerreiro et al., 2013; Jonsson et al., 2013; Lambert et al., 2013; Singleton and Hardy, 2016).”

“In addition, genome-wide association studies have implicated a wider range of biological functions that likely contribute to risk of AD, in particular innate immunity and inflammation (Cuyvers and Sleegers, 2016; Guerreiro et al., 2013; Jonsson et al., 2013; Lambert et al., 2013; Singleton and Hardy, 2016).”

“In mammals, ∼20,000 of such ‘master clock’ neurons reside within the suprachiasmatic nucleus (SCN) (see Glossary, Box 1) of the hypothalamus (Dibner et al., 2010).”

“Not only will the rodents’ activity shift to realign with the expected mealtime, but the timing of clock gene expression in peripheral tissue will also be shifted by the daytime feeding schedule (Boulos and Terman, 1980; Damiola et al., 2000; Stokkan et al., 2001).”

“…and synchronized oscillation of the central clock with the various peripheral tissue clocks is thought to optimally coordinate an organism’s metabolism (Bass and Takahashi, 2010), supporting its health and fitness (Nedeltcheva and Scheer, 2014; Roenneberg and Merrow, 2016; Scheer et al., 2009).”

“…organisms that carry clock gene mutations that abolish molecular rhythmicity, such as mutations in Bmal1 in mice (Bunger et al., 2000; Laposky et al., 2005) or in period ( per0) in flies (Konopka and Benzer, 1971), might not be the optimal models in which to study age-related circadian deficits.”

“1 for a comparison of the mammalian and Drosophila molecular clocks) (Hardin and Panda, 2013; Mohawk et al., 2012).”

“Genetic linkage studies in familial AD (Goate et al., 1991; Rogaev et al., 1995; Sherrington et al., 1995) and wholegenome studies of the more common, sporadic form of AD (Jonsson et al.”

“…and synchronized oscillation of the central clock with the various peripheral tissue clocks is thought to optimally coordinate an organism’s metabolism (Bass and Takahashi, 2010), supporting its health and fitness (Nedeltcheva and Scheer, 2014; Roenneberg and Merrow, 2016; Scheer et al., 2009).”

“…accompanied by phosphorylation of the corresponding signalling proteins, such as the insulin receptor substrate 2 (Irs2), which is a hallmark of suppressed insulin signalling (Holscher, 2014a; Kleinridders, 2016; Moloney et al., 2010a; Rivera et al., 2005; Steen et al., 2005; Talbot et al., 2012).”

“…in familial AD (Goate et al., 1991; Rogaev et al., 1995; Sherrington et al., 1995) and wholegenome studies of the more common, sporadic form of AD (Jonsson et al., 2012) indicate that the increased production of aggregationprone Aβ peptides, the main component of plaques (Glenner and Wong, 1984;…”

“…accompanied by phosphorylation of the corresponding signalling proteins, such as the insulin receptor substrate 2 (Irs2), which is a hallmark of suppressed insulin signalling (Holscher, 2014a; Kleinridders, 2016; Moloney et al., 2010a; Rivera et al., 2005; Steen et al., 2005; Talbot et al., 2012).”

“For this reason, model organisms that carry clock gene mutations that abolish molecular rhythmicity, such as mutations in Bmal1 in mice (Bunger et al., 2000; Laposky et al., 2005) or in period ( per) in flies (Konopka and Benzer, 1971), might not be the optimal models in which to study age-related circadian deficits.”

“For example, Aβ in the ISF is higher during wakefulness in mice, representing periods of peak neuronal activity (Bero et al., 2011), and lowest during sleep (Huang et al., 2012; Kang et al., 2009) or under anaesthesia (Brody et al., 2008).”

“(Hutton et al., 1998) (Spillantini et al., 1998) (Spillantini and Goedert, 2013) D is ea se M o d el s & M ec h an is m s fat body (see Glossary, Box 1) (Xu et al., 2008).”

“Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein.”

“(Hardy, 1997) (Citron et al., 1997) (Braak and Braak, 1994) PSEN1; PSEN2 Presenilin 1; presenilin 2 PSEN1 and PSEN2 are subunits of the γ-secretase catalytic complex.”

“(Hardy, 1997) (Citron et al., 1997) (Braak and Braak, 1994) PSEN1; PSEN2 Presenilin 1; presenilin 2 PSEN1 and PSEN2 are subunits of the γ-secretase catalytic complex.”

“, 2017) and those undertaking shift work (Kecklund and Axelsson, 2016; Knutsson, 2003; Pan et al., 2011).”

“Indeed, individuals with type II diabetes who also carry the ε4 APOE allele are over five times more likely to develop AD than are those with neither diabetes nor the ε4 allele (Peila et al., 2002).”

“(Hutton et al., 1998) (Spillantini et al., 1998) (Spillantini and Goedert, 2013) D is ea se M o d el s & M ec h an is m s fat body (see Glossary, Box 1) (Xu et al., 2008).”

“…1995; Sherrington et al., 1995) and wholegenome studies of the more common, sporadic form of AD (Jonsson et al., 2012) indicate that the increased production of aggregationprone Aβ peptides, the main component of plaques (Glenner and Wong, 1984; Masters et al., 1985a,b), might initiate the disease.”

“…and synchronized oscillation of the central clock with the various peripheral tissue clocks is thought to optimally coordinate an organism’s metabolism (Bass and Takahashi, 2010), supporting its health and fitness (Nedeltcheva and Scheer, 2014; Roenneberg and Merrow, 2016; Scheer et al., 2009).”

“Sleep disruption and risk of amyloid pathology As recounted above and elsewhere (Holth et al., 2017; Ju et al., 2014; Musiek and Holtzman, 2016; Musiek et al., 2015), neurodegenerative disease results in the loss of restorative sleep, which might in turn accentuate the pathological processes that contribute to AD.”

“βOHB is the most abundant circulating ketone body and serves as an alternative energy source for tissues, including the brain, when glucose levels are low (Newman and Verdin, 2014).”

“Other zeitgebers include nonphotic stimuli, such as temperature, food availability, exercise and social interactions (Buhr et al., 2010; Carneiro and Araujo, 2012; Glaser and Stanewsky, 2007; Hastings et al., 1998; Levine et al., 2002a; Mistlberger and Skene, 2005; Simoni et al., 2014), which under certain circumstanc…”

“Sleep disruption and risk of amyloid pathology As recounted above and elsewhere (Holth et al., 2017; Ju et al., 2014; Musiek and Holtzman, 2016; Musiek et al., 2015), neurodegenerative disease results in the loss of restorative sleep, which might in turn accentuate the pathological processes that contribute to AD.”

“In humans, poor sleep patterns, even in the absence of overt neurodegenerative disease, are a risk factor for the metabolic syndrome and for subsequent type II diabetes (Bass and Takahashi, 2010; Pan et al., 2011; Spiegel et al., 2009; Yaggi et al., 2006).”

“These pathological features have been replicated to some extent in vertebrate and invertebrate model organisms (Drummond and Wisniewski, 2017; Moloney et al., 2010b).”

“, 2017) and those undertaking shift work (Kecklund and Axelsson, 2016; Knutsson, 2003; Pan et al., 2011).”

“In humans, poor sleep patterns, even in the absence of overt neurodegenerative disease, are a risk factor for the metabolic syndrome and for subsequent type II diabetes (Bass and Takahashi, 2010; Pan et al., 2011; Spiegel et al., 2009; Yaggi et al., 2006).”

“The neurodegenerative disease we focus on in this review is AD, which is characterized histologically by the dual pathologies of extracellular neuritic (amyloid β, Aβ) plaques (Braak and Braak, 1994) and intraneuronal neurofibrillary tangles (see Table 1 and Glossary, Box 1) (Braak et al., 1994).”

“These pathological features have been replicated to some extent in vertebrate and invertebrate model organisms (Drummond and Wisniewski, 2017; Moloney et al., 2010b).”

“Similar changes in the human brain during sleep would favour the bulk flow of CSF and ISF through the perivascular (Rennels et al., 1985) and glymphatic drainage channels (Iliff et al.”

“…accompanied by phosphorylation of the corresponding signalling proteins, such as the insulin receptor substrate 2 (Irs2), which is a hallmark of suppressed insulin signalling (Holscher, 2014a; Kleinridders, 2016; Moloney et al., 2010a; Rivera et al., 2005; Steen et al., 2005; Talbot et al., 2012).”

“This was demonstrated in a mouse model in which the liver clock was specifically suppressed, resulting in all but a handful of genes losing their circadian regulation (Kornmann et al., 2007).”

“The structural integrity of the glymphatic channels, as reported by the polarized perivascular expression of aquaporin 4 (AQP4), declines with age and more so when accompanied by amyloid pathology (Zeppenfeld et al., 2017).”

“In this way, light infiltrating the fly’s cuticle directly synchronizes the central circadian clock, as well as the peripheral oscillators (Plautz et al., 1997) (see Fig.”

“Exploring the utility of βOHB as a potential nonphotic zeitgeber could be particularly valuable for AD, given the deficit in brain glucose metabolism noted above (Cunnane et al., 2011).”

“As many as 90% of individuals diagnosed with REM sleep behaviour disorder will go on to develop a neurodegenerative disease associated with α-synuclein aggregation (Boeve et al., 2001; Iranzo et al., 2014).”

“D is ea se M o d el s & M ec h an is m s (Kewley et al., 2004)] transcription factors, such as those encoded by the genes Bmal1 (Arntl) and Clock.”

“Meanwhile, the SCN remains entrained to the light-dark cycle under most conditions (Hara et al., 2001).”

“In Drosophila, there have been similar findings, in particular the boosting of the cleavage of APPL (theDrosophila orthologue of APP) by β-secretase resulted in behavioural arrhythmia and reduced the expression of the clock gene per (Blake et al., 2015).”

“As many as 90% of individuals diagnosed with REM sleep behaviour disorder will go on to develop a neurodegenerative disease associated with α-synuclein aggregation (Boeve et al., 2001; Iranzo et al., 2014).”

“Sleep disruption and risk of amyloid pathology As recounted above and elsewhere (Holth et al., 2017; Ju et al., 2014; Musiek and Holtzman, 2016; Musiek et al., 2015), neurodegenerative disease results in the loss of restorative sleep, which might in turn accentuate the pathological processes that contribute to AD.”

“Central to metabolic health is the synchronization of gut, liver and muscle metabolic cycles and their interplay with the glucocorticoid hormones secreted by the hypothalamus-pituitary-adrenal axis (see Glossary, Box 1) (Dickmeis, 2009; Gamble et al., 2014; Reddy et al., 2007).”

“The damage to the hippocampus has been likened to accelerated ageing, likely mediated by astrogliosis and increased production of reactive oxygen species (Ali et al., 2015; Musiek et al., 2013).”

“In the periphery, the fat body derived cytokine, Unpaired 2 (Upd2), conveys the fed status in Drosophila to the insulin-producing cells (IPCs) in the brain (Rajan and Perrimon, 2012).”

“Central to metabolic health is the synchronization of gut, liver and muscle metabolic cycles and their interplay with the glucocorticoid hormones secreted by the hypothalamus-pituitary-adrenal axis (see Glossary, Box 1) (Dickmeis, 2009; Gamble et al., 2014; Reddy et al., 2007).”

“Such ageing demographic trends, along with the disruptive effects of the modern environment, such as bright light at night and shift work, could result in a population predisposed to circadian dysfunction (Antunes et al., 2010).”

“The resulting animals show decreased brain size accompanied by an increase in tau phosphorylation (Schubert et al., 2003), an observation that is concordant with the tau hyperphosphorylation observed in the brains of AD patients.”

“Less robust circadian signalling with age might underpin age- related sleep deficits, which might, in turn, directly injure the brain (Kondratova and Kondratov, 2012).”

“Activating this mediator of innate immunity, which classically responds to bacteria-derived lipopolysaccharide, likely enhances the proinflammatory environment in the brain in AD (Balducci et al., 2010; Huang et al., 2017).”

“Notably, visual photic signals, meaning perceived visual inputs, act as a relatively minor entraining stimulus in mammals (Hankins et al., 2008) and Drosophila (Rieger et al.”

“The link between sleep disorders and Parkinson’s disease is arguably even stronger, with rapid eye movement (REM) sleep behaviour disorder (see Glossary, Box 1) preceding classical Parkinsonian features by decades in some instances (Postuma and Berg, 2016).”

“The negative effects of chronic circadian misalignment is evident in shift workers, who have an increased risk for obesity, type 2 diabetes and cardiovascular disease (Antunes et al., 2010; Haus and Smolensky, 2006; Pan et al., 2011; Scheer et al., 2009).”

“, 2014) and mouse (Nakamura et al., 2011), indicate that communication between clock neurons, and between clock neurons and their output pathways, fails earlier than does the circadian cycling of the molecular components of the clock.”

“…food availability, exercise and social interactions (Buhr et al., 2010; Carneiro and Araujo, 2012; Glaser and Stanewsky, 2007; Hastings et al., 1998; Levine et al., 2002a; Mistlberger and Skene, 2005; Simoni et al., 2014), which under certain circumstances can entrain endogenous rhythmicity.”

“…effects, including excessive daytime sleepiness, anticholinergic effects, such as D is ea se M o d el s & M ec h an is m s mouth dryness and urinary retention, and, in the case of antipsychotics, increased mortality (Camargos et al., 2011, 2012, 2014; Kales et al., 2012; McCleery et al., 2016).”

“…first, there is less differentiation between day and night and second, the oscillations are phase shifted so that peaks in both body temperature and activity occur later in the day as compared to healthy controls (Harper et al., 2001; Satlin et al., 1995; Tranah et al., 2011; Volicer et al., 2001).”

“As a recent meta-analysis confirmed, light therapy is effective in improving sleep-wake deficits, at least in women; however, the effect sizes are small (van Maanen et al., 2016).”

“Not only will the rodents’ activity shift to realign with the expected mealtime, but the timing of clock gene expression in peripheral tissue will also be shifted by the daytime feeding schedule (Boulos and Terman, 1980; Damiola et al., 2000; Stokkan et al., 2001).”

“In health, a host of hepatic genes, including many involved in metabolism (Schmutz et al., 2010), exhibit circadian transcriptional regulation (Delezie and Challet, 2011).”

“Concordant with these observations, Liguori and colleagues found that individuals with AD had elevated levels of orexin over controls, and that these increased levels correlated positively with both sleep deficits and cognitive decline (Liguori et al., 2014).”

“, 2012), and in long-haul aircrew, jet lag has been linked to reduced hippocampal volume (Cho, 2001).”

“In population-based studies, diabetes is an established risk factor for accelerated age-related cognitive decline (Allen et al., 2004), for dementia as a syndrome (Biessels et al., 2006) and for AD in particular (Huang et al., 2014; Kopf and Frölich, 2009; Wang et al., 2012).”

“(Hutton et al., 1998) (Spillantini et al., 1998) (Spillantini and Goedert, 2013) D is ea se M o d el s & M ec h an is m s fat body (see Glossary, Box 1) (Xu et al., 2008).”

“…advances in metabolic medicine using, for example, glucagon-like peptide 1 (GLP1, also known as GCG) analogues to reverse insulin resistance and to reduce neuroinflammation, should be further investigated in the context of neurodegenerative disease (Aviles-Olmos et al., 2014; Holscher, 2014b).”

“For example, Aβ in the ISF is higher during wakefulness in mice, representing periods of peak neuronal activity (Bero et al., 2011), and lowest during sleep (Huang et al., 2012; Kang et al., 2009) or under anaesthesia (Brody et al., 2008).”

“Such outcomes resemble the features of the metabolic syndrome (Sperling et al., 2015), characterized in humans by insulin resistance, abdominal obesity, abnormal lipids and hypertension, which is linked to type II diabetes.”

“…accompanied by phosphorylation of the corresponding signalling proteins, such as the insulin receptor substrate 2 (Irs2), which is a hallmark of suppressed insulin signalling (Holscher, 2014a; Kleinridders, 2016; Moloney et al., 2010a; Rivera et al., 2005; Steen et al., 2005; Talbot et al., 2012).”

“1A) (Koh et al., 2006; Peschel et al., 2009).”

“Given the importance of circadian biology in regulating organismal health, it is of no surprise that the breakdown of daily circadian rhythms (see Glossary, Box 1) is a risk factor for a range of diseases, including metabolic syndrome, vascular disease and cancer (Anea et al., 2009; Bass and Takahashi, 2010; Evans and…”

“Trazodone might also have an unexpected beneficial role in suppressing excessive ER stress signaling, at least in murine models of prion disease and tauopathy (Halliday et al., 2017).”

“toxicity are typically generated by expressing the Aβ peptide downstream of a secretion signal peptide (Crowther et al., 2005; Finelli et al., 2004; Iijima et al., 2004).”

“In addition, genome-wide association studies have implicated a wider range of biological functions that likely contribute to risk of AD, in particular innate immunity and inflammation (Cuyvers and Sleegers, 2016; Guerreiro et al., 2013; Jonsson et al., 2013; Lambert et al., 2013; Singleton and Hardy, 2016).”

“For example, Aβ in the ISF is higher during wakefulness in mice, representing periods of peak neuronal activity (Bero et al., 2011), and lowest during sleep (Huang et al., 2012; Kang et al., 2009) or under anaesthesia (Brody et al., 2008).”

“AQP4 likely mediates water influx into the glymphatic system, facilitating its flow, and is itself under circadian control (Zuber et al., 2009).”

“Remarkably, similar studies in ageing Drosophila have shown that daytime-only feeding consolidates the sleep/wake cycle and slows age-related degeneration, at least in cardiac function (Gill et al., 2015).”

“…stress (Cretenet et al., 2010; Maillo et al., 2017), and by the associated oxidative and glycation damage that promotes a neuroinflammatory response, which is likely mediated by activated microglia (Catrysse and van D is ea se M o d el s & M ec h an is m s Loo, 2017; Villegas-Llerena et al., 2016).”

“Other zeitgebers include nonphotic stimuli, such as temperature, food availability, exercise and social interactions (Buhr et al., 2010; Carneiro and Araujo, 2012; Glaser and Stanewsky, 2007; Hastings et al., 1998; Levine et al., 2002a; Mistlberger and Skene, 2005; Simoni et al., 2014), which under certain circumstanc…”

“In population-based studies, diabetes is an established risk factor for accelerated age-related cognitive decline (Allen et al., 2004), for dementia as a syndrome (Biessels et al., 2006) and for AD in particular (Huang et al., 2014; Kopf and Frölich, 2009; Wang et al., 2012).”

“However, amyloid plaques are relatively sparse in the SCN in AD (Stopa et al., 1999), excluding bulk Aβ deposition as the cause of D is ea se M o d el s & M ec h an is m s neurodegeneration.”

“By contrast, in the presence of functioning peripheral clocks, centrally derived signals, such as glucocorticoid hormones, are sufficient to entrain efficiently most circadian gene expression in tissues (Reddy et al., 2007).”

“These findings indicate that specific neurodegenerative lesions in the SCN might cause circadian deficits, a hypothesis that finds some support in human histopathological studies (Swaab et al., 1988; Zhou et al., 1995).”

“…food availability, exercise and social interactions (Buhr et al., 2010; Carneiro and Araujo, 2012; Glaser and Stanewsky, 2007; Hastings et al., 1998; Levine et al., 2002a; Mistlberger and Skene, 2005; Simoni et al., 2014), which under certain circumstances can entrain endogenous rhythmicity.”

“…first, there is less differentiation between day and night and second, the oscillations are phase shifted so that peaks in both body temperature and activity occur later in the day as compared to healthy controls (Harper et al., 2001; Satlin et al., 1995; Tranah et al., 2011; Volicer et al., 2001).”

“Orexin knockout mice sleep more than controls (Chemelli et al., 1999), and when crossed with APP/ PSEN1 mice, they exhibit a marked reduction in Aβ plaque deposition (Roh et al., 2014).”

“…first, there is less differentiation between day and night and second, the oscillations are phase shifted so that peaks in both body temperature and activity occur later in the day as compared to healthy controls (Harper et al., 2001; Satlin et al., 1995; Tranah et al., 2011; Volicer et al., 2001).”

“In population-based studies, diabetes is an established risk factor for accelerated age-related cognitive decline (Allen et al., 2004), for dementia as a syndrome (Biessels et al., 2006) and for AD in particular (Huang et al., 2014; Kopf and Frölich, 2009; Wang et al., 2012).”

“In Drosophila, 150 central clock gene-expressing neurons are subdivided into seven groups that are located in the anterior, posterior and superior brain (Peschel and Helfrich-Förster, 2011).”

“, 2010; Glaser and Stanewsky, 2007), food availability (Carneiro and Araujo, 2012), exercise (Atkinson et al., 2007; Edgar and Dement, 1991; Miyazaki et al., 2001) and social interactions (Hastings et al.”

“Notably, visual photic signals, meaning perceived visual inputs, act as a relatively minor entraining stimulus in mammals (Hankins et al., 2008) and Drosophila (Rieger et al., 2003).”

“The main features include increased night-timewakefulness, caused by increased sleep latency and reduced sleep consolidation (the duration of uninterrupted sleep episodes), reduced slow-wave sleep and increased day-time naps (Bonanni et al., 2005; Musiek et al., 2015).”

“The desynchronization of the central and peripheral clocks can occur as a result of modern life, as seen in individuals exposed to lightemitting diode (LED) light at night (Hatori et al., 2017) and those undertaking shift work (Kecklund and Axelsson, 2016; Knutsson, 2003; Pan et al.”

“In the mouse, elevated glucose levels are observed to interact with both age and Aβ pathology by increasing the levels of the Aβ peptide in the hippocampal ISF; the induced Aβ elevation was most marked in aged mice that had extensive plaque pathology (Macauley et al., 2015).”

“…KM670/671NL, the PSEN1 variant, M146V, and theMAPT variant, P301L) exhibit decreased nocturnal activity (the equivalent of daytime napping in a nocturnal species), increased daytime activity (Sterniczuk et al., 2010) and age-related changes in body temperature rhythms (Knight et al., 2013).”

“According to each organism’s ecological niche, activities such as sleeping, eating, mating and predation-avoidance are optimally performed either during the day or night (Hut et al., 2012).”

“In particular, mouse and Drosophila models of Huntington’s disease (Pallier et al., 2007) and AD (Chen et al.”

“1 for a comparison of the mammalian and Drosophila molecular clocks) (Hardin and Panda, 2013; Mohawk et al., 2012).”

“, 2016); it has also been noted to cause circadian dysfunction from an early stage (Osorio et al., 2011; Tranah et al., 2011).”

“In diabetes, Aβ pathogenesis might also be enhanced as a consequence of endoplasmic reticulum (ER) stress (Cretenet et al., 2010; Maillo et al., 2017), and by the associated oxidative and glycation damage that promotes a neuroinflammatory response, which is likely mediated by activated microglia (Catrysse and van Brai…”

“The relative timings (phase relationships) of sleep and of other circadian oscillations, such as body temperature, also change with age (Yoon et al., 2003), likely indicating differences in entrainment communication between various clocks.”

“Typically, older individuals nap more often during the day (Buysse et al., 1992) and experience shallower night-time sleep with more arousals, which disrupt non-rapid eye movement sleep in A Drosophila Murine B A Drosophila MurineB Light Light Insulin Insulin Liver Fat body Adipocyte…”

“Melatonin is secreted from the pineal gland, beginning in the early evening and reaching peak concentrations soon after midnight (Wehr et al., 2001).”

“The neurodegenerative disease we focus on in this review is AD, which is characterized histologically by the dual pathologies of extracellular neuritic (amyloid β, Aβ) plaques (Braak and Braak, 1994) and intraneuronal neurofibrillary tangles (see Table 1 and Glossary, Box 1) (Braak et al.”

“, 2010; Glaser and Stanewsky, 2007), food availability (Carneiro and Araujo, 2012), exercise (Atkinson et al., 2007; Edgar and Dement, 1991; Miyazaki et al., 2001) and social interactions (Hastings et al.”

“Their conclusion was that the central, and indeed the secondary, brain clocks were rhythmic in healthy individuals and in those with AD, but in the latter there were marked phase shifts, indicating changes in their relative synchronization (Cermakian et al., 2011).”

“For example, in human brain tissue from individuals with AD post mortem, the expression of clock genes in the pineal, a structure that receives central clock inputs, was found to be similar to the gene expression changes seen in rats in which the SCN-pineal projection had been experimentally lesioned (Wu et al., 2006).”

“, 2009) and the triple transgenic (3×TgAD) mouse models (Di Meco et al., 2014; Rothman et al., 2013).”

“…week-long study, the daytime-fed mice gained more adipose tissue, were less physically active, exhibited increased levels of plasma insulin, and accumulated more triglycerides and cholesterol in their liver as compared to mice fed the same diet but during their active phase (Yasumoto et al., 2016).”

“, 2006) and in vivo (Wyse and Coogan, 2010) models of ageing indicate that the molecular clock might also be impaired in aged cells and organisms, the extent to which this contributes to circadian changes in elderly humans (Münch et al.”

“…potential candidates include temperature (Buhr et al., 2010; Glaser and Stanewsky, 2007), food availability (Carneiro and Araujo, 2012), exercise (Atkinson et al., 2007; Edgar and Dement, 1991; Miyazaki et al., 2001) and social interactions (Hastings et al., 1998; Levine et al., 2002b;…”

“…effects, including excessive daytime sleepiness, anticholinergic effects, such as D is ea se M o d el s & M ec h an is m s mouth dryness and urinary retention, and, in the case of antipsychotics, increased mortality (Camargos et al., 2011, 2012, 2014; Kales et al., 2012; McCleery et al., 2016).”

“Sleep disruption and risk of amyloid pathology As recounted above and elsewhere (Holth et al., 2017; Ju et al., 2014; Musiek and Holtzman, 2016; Musiek et al., 2015), neurodegenerative disease results in the loss of restorative sleep, which might in turn accentuate the pathological processes that contribute to AD.”

“However, metabolic hormones such as glucocorticoids, ghrelin, leptin, insulin, glucagon and glucagon-like peptide-1 (GLP1), which exhibit daily rhythms of synthesis and secretion, are all proposed zeitgebers for circadian oscillators (GilLozano et al., 2014; Patton and Mistlberger, 2013).”

“D is ea se M o d el s & M ec h an is m s particular (Dijk et al., 2001).”

“Despite the relatively mild circadian deficits observed in murine models of AD (Coogan et al., 2013), one study has shown that in a knock-in mouse model of human APP/PSEN1 genes, the mice have a reduced amplitude of endogenous Per2 mRNA oscillation in the SCN (Duncan et al., 2012).”

“…vitro (Kunieda et al., 2006) and in vivo (Wyse and Coogan, 2010) models of ageing indicate that the molecular clock might also be impaired in aged cells and organisms, the extent to which this contributes to circadian changes in elderly humans (Münch et al., 2005; Schmidt et al., 2012) is unclear.”

“In this regard, sleep-inducing GABA agonists have been shown to improve cognitive dysfunction in Drosophila that express presenilin variants linked to AD in humans (Dissel et al., 2015).”

“In population-based studies, diabetes is an established risk factor for accelerated age-related cognitive decline (Allen et al., 2004), for dementia as a syndrome (Biessels et al., 2006) and for AD in particular (Huang et al., 2014; Kopf and Frölich, 2009; Wang et al., 2012).”

“…vitro (Kunieda et al., 2006) and in vivo (Wyse and Coogan, 2010) models of ageing indicate that the molecular clock might also be impaired in aged cells and organisms, the extent to which this contributes to circadian changes in elderly humans (Münch et al., 2005; Schmidt et al., 2012) is unclear.”

“Considering the primary importance of photic entrainment of the SCN, initial studies employed light as a therapy, typically providing a bright environment during the day and usually combined with darkness at night (Fetveit et al., 2003; Lack et al., 2005; Pallesen et al., 2005; Sharkey et al., 2011).”

“Although upstream factors could affect the function of the SCN, the authors concluded that the results were consistent with a failure of the SCN to entrain downstream oscillators (Maywood et al., 2010; Pallier et al., 2007).”

“As many as 90% of individuals diagnosed with REM sleep behaviour disorder will go on to develop a neurodegenerative disease associated with α-synuclein aggregation (Boeve et al., 2001; Iranzo et al., 2014).”

“In this regard, melatonin has been trialled as a therapeutic for AD because of its use, with uncertain clinical evidence, for treating insomnia and jetlag in otherwise healthy individuals (Costello et al., 2014; PandiPerumal et al., 2007).”

“These pathological features have been replicated to some extent in vertebrate and invertebrate model organisms (Drummond and Wisniewski, 2017; Moloney et al., 2010b).”

“Remarkably, similar studies in ageing Drosophila have shown that daytime-only feeding consolidates the sleep/wake cycle and slows age-related degeneration, at least in cardiac function (Gill et al., 2015).”

“While in vitro (Kunieda et al., 2006) and in vivo (Wyse and Coogan, 2010) models of ageing indicate that the molecular clock might also be impaired in aged cells and organisms, the extent to which this contributes to circadian changes in elderly humans (Münch et al.”

“Considering the primary importance of photic entrainment of the SCN, initial studies employed light as a therapy, typically providing a bright environment during the day and usually combined with darkness at night (Fetveit et al., 2003; Lack et al., 2005; Pallesen et al., 2005; Sharkey et al., 2011).”

“Recently, liver-derived beta-hydroxybutyrate (βOHB) was identified as an important nonphotic zeitgeber in a study that used mice with liver- and brain-specific Per2 deletions (Chavan et al., 2016).”

“…such as temperature, food availability, exercise and social interactions (Buhr et al., 2010; Carneiro and Araujo, 2012; Glaser and Stanewsky, 2007; Hastings et al., 1998; Levine et al., 2002a; Mistlberger and Skene, 2005; Simoni et al., 2014), which under certain circumstances can entrain…”

“Activating this mediator of innate immunity, which classically responds to bacteria-derived lipopolysaccharide, likely enhances the proinflammatory environment in the brain in AD (Balducci et al., 2010; Huang et al., 2017).”

“Peripheral clock arrhythmia and diabetes Disturbed clocks in the brain have deleterious consequences for the whole organism, disrupting directly, or indirectly, the concerted hormonal, autonomic and metabolic functioning of various organ systems (Delezie and Challet, 2011; Reddy and Maywood, 2007) (Fig.”

“Centrally, a subset of clock (DN1) neurons regulates the secretion of insulin-like peptide (ILP) in a circadian pattern, which in turn regulates fat body-mediated sugar homeostasis (Barber et al., 2016) (Fig.”

“Unfortunately, these insights have not translated well into the clinic because therapeutic trials of melatonin have yielded little to no improvement in the sleep of individuals with AD (McCleery et al., 2016; Xu et al., 2015).”

“, 2013), one study has shown that in a knock-in mouse model of human APP/PSEN1 genes, the mice have a reduced amplitude of endogenous Per2 mRNA oscillation in the SCN (Duncan et al., 2012).”

“The circadian consequences of overexpressing APP or Aβ include abnormalities in sleep, locomotor and body temperature rhythms (Ambrée et al., 2006; Gorman and Yellon, 2010;Wisor et al., 2005).”

“There is some evidence that leptin and ghrelin can modulate food-entrained rhythms, acting peripherally but also through feedback to hypothalamic circuits in the brain (Escobar et al., 2009; Lockie, 2013).”

“…genome-wide association studies have implicated a wider range of biological functions that likely contribute to risk of AD, in particular innate immunity and inflammation (Cuyvers and Sleegers, 2016; Guerreiro et al., 2013; Jonsson et al., 2013; Lambert et al., 2013; Singleton and Hardy, 2016).”

“In healthy humans, even acute sleep deprivation is sufficient to cause detectable neuronal damage, as reflected by the presence of markers of neuronal and of blood-brain barrier damage in the blood of healthy volunteers (Benedict et al., 2014).”

“Light is the primary zeitgeber and, as such, is primarily responsible for entraining the endogenous rhythmicity of an organism’s neural circuits so that they oscillate in synchrony with their environment (Münch and Bromundt, 2012).”

“In diabetes, Aβ pathogenesis might also be enhanced as a consequence of endoplasmic reticulum (ER) stress (Cretenet et al., 2010; Maillo et al., 2017), and by the associated oxidative and glycation damage that promotes a neuroinflammatory response, which is likely mediated by activated microglia (Catrysse and van Brai…”

“Orexin antagonists are already being investigated for treatment of primary insomnia (Kishi et al., 2015); perhaps now they can be trialled for the bigger prize of disease modification in neurodegenerative disease.”

“Considering the primary importance of photic entrainment of the SCN, initial studies employed light as a therapy, typically providing a bright environment during the day and usually combined with darkness at night (Fetveit et al., 2003; Lack et al., 2005; Pallesen et al., 2005; Sharkey et al., 2011).”

“By contrast, mice that express either of two human tau variants that contain disease-linked substitutions (P301L and R406W) exhibit abnormalities in a sleep electroencephalogram but no disruption to their circadian rhythms (Koss et al., 2016).”

“These clock genes are responsible for circadian oscillations at the cellular level by regulating membrane electrical activity and cellular metabolism (O’Neill and Feeney, 2014; O’Neill and Reddy, 2012).”

“…accompanied by phosphorylation of the corresponding signalling proteins, such as the insulin receptor substrate 2 (Irs2), which is a hallmark of suppressed insulin signalling (Holscher, 2014a; Kleinridders, 2016; Moloney et al., 2010a; Rivera et al., 2005; Steen et al., 2005; Talbot et al., 2012).”

“If the output of the SCNwere defective in AD, then this result would be expected since the light-entrained central clock would be functional but (as discussed above) unable to communicate effectively with other brain clocks and with the periphery.”

“The damage to the hippocampus has been likened to accelerated ageing, likely mediated by astrogliosis and increased production of reactive oxygen species (Ali et al., 2015; Musiek et al., 2013).”

“Evidence of the FEO power as an entraining factor has come from experiments in rodents in which daytime feeding, which is antiphase in a nocturnal species, was sufficient to entrain the animals to a new, anticipatory sleep/ wake cycle (Carneiro and Araujo, 2012).”

“…KM670/671NL, the PSEN1 variant, M146V, and theMAPT variant, P301L) exhibit decreased nocturnal activity (the equivalent of daytime napping in a nocturnal species), increased daytime activity (Sterniczuk et al., 2010) and age-related changes in body temperature rhythms (Knight et al., 2013).”

“For example, chronic ‘jet lag’ in rodents causes deficits in hippocampal neurogenesis (Rakai et al., 2014) and cognition (Kott et al., 2012), and in long-haul aircrew, jet lag has been linked to reduced hippocampal volume (Cho, 2001).”

“Interestingly, a subset of IPCs has been shown to regulate sleep-wake behaviour in Drosophila (Yurgel et al., 2015).”

“Perhaps smaller, soluble Aβ species are responsible instead, as suggested by the transplantation of PC12 cells that express a disease-linked APP variant into rats; the transplantation of these cells (but not of control PC12 cells) causes circadian deficits (Tate et al., 1992).”

“These clock genes are responsible for circadian oscillations at the cellular level by regulating membrane electrical activity and cellular metabolism (O’Neill and Feeney, 2014; O’Neill and Reddy, 2012).”

“Additionally, individuals with moderate and advanced AD may exhibit ‘sundowning’, where agitation is more marked in the late afternoon (Bedrosian and Nelson, 2013; Volicer et al., 2001).”

“…effects, including excessive daytime sleepiness, anticholinergic effects, such as D is ea se M o d el s & M ec h an is m s mouth dryness and urinary retention, and, in the case of antipsychotics, increased mortality (Camargos et al., 2011, 2012, 2014; Kales et al., 2012; McCleery et al., 2016).”

“Similarly, Drosophila that express human Aβ as a model of AD show progressive behavioural arrhythmia, despite the essentially normal oscillation of their central molecular clock (as shown by the use of a luciferase reporter) (Chen et al., 2014).”

“Given that the liver is the main peripheral organ communicating with brain via the liver-brain axis, the liver might affect Aβ clearance by regulating the circadian rhythm [91].”

“Overexpression of TFEB in mouse models of AD also reduced the number of protein deposits and alleviated behavioral abnormalities [99] [100].”

“, amyloid deposition, oxidative stress and cell death) that in turn leads to a further disruption of the circadian timing system [122, 123, 127].”

“In neurodegenerative diseases, significant impairments in different parts of this circadian neuronal network have been documented and have been recently reviewed elsewhere (Chauhan et al., 2017; Fifel, 2017; Fifel and DeBoer, 2020; Fifel and Videnovic, 2020).”

“There is accumulating evidence that circadian rhythmicity is altered in AD (Chauhan et al., 2017).”

“Aβ levels exhibited diurnal fluctuations in both the cerebrospinal fluid (CSF) and interstitial fluid (ISF), the clearance and aggregation of which were regulated by circadian rhythms [99,102].”

“How alterations in these peripheral oscillators may contribute to AD is an important question that has been considered in recent reviews (Chauhan et al., 2017; Kent, 2014).”

“Senescent-related alteration in clock function are often milder compared to deficits seen in neurodegenerative diseases like Alzheimer's disease (AD; Chauhan et al., 2017; Leng et al., 2019).”

“sleep and metabolism may increase the susceptibility of the brain to further degeneration [62].”

“Interestingly, new evidence suggests that the circadian clock may be heavily involved in this effect of AD on sleep (Chauhan et al., 2017; Musiek et al., 2018; Hablitz et al., 2020; Clark et al., 2022; Hoyt and Obrietan, 2022).”

“Circadian disruption in AD may create a self-reinforcing feedback loop that promotes pathologies such as amyloid deposition, oxidative stress, and cell death, which further disrupt circadian rhythms [12, 15, 16].”

“TRF promotes circadian clock synchronization between central and peripheral clocks and enhances cognitive function by maintaining glucose metabolism and reducing a b accumulation 157 .”

“There is clear evidence that circadian rhythms are impaired in AD patients (Chauhan et al., 2017; Homolak et al., 2018; Hoyt & Obrietan, 2022; Rigat et al., 2023).”

“Amismatch between themaster clock and peripheral time keepers have been suggested as involved in neurodegenerative diseases like Alzheimer’s and Parkinson’s, characterized also by sleep disturbances as early symptoms (Chauhan et al. 2017).”

“We conducted several heuristic procedures to provide a set of approximate solutions for the tour Γ̂ defined in (7).”

“In the case of AD, it has been found that if the neurodegeneration starts in the regulatory region of sleep and circadian rhythm, then neurons are much more susceptible to the degradation process [23].”

“For the semihierarchical model (Figure 1(b)), O1 and O2 could represent the central and peripheral clocks in Drosophila, since in flies the clock protein cryptochrome is a photoreceptor and thus even peripheral organs receive some direct light input [11].”

“Circadian disturbance and AD may be a reciprocal causation: neurodegeneration likely impairs circadian rhythms either by dysfunctional SCN neuron or abnormal communication between the central clock with the peripheral tissues (Chauhan et al., 2017; Van Erum et al., 2018).”

“…that coordinates multiple physiological processes, including hormone secretion, energy metabolism, immune processes, etc. Accumulating evidence shows that circadian rhythm disruption (CRD) was commonly observed to contribute to cognitive impairment and might increase Aβ burden in AD context [8, 9].”

“There are reports on clearance during night sleep of aggregates formed during the day (Chauhan et al., 2017).”

“Doch inzwischen zeigt sich, dass sie auch ein wichtiger kausaler Faktor bei der Entwicklung solcher Krankheiten sind, v. a. bei der Alzheimer-Krankheit (vgl. Chauhan et al. 2017; Harris et al. 2021; Peng et al. 2022), aber auch bei Parkinson (vgl. Leng et al. 2019).”

“Therefore, model system carrying clock gene deletion have limitations in representing the pathological changes occurring to clock components or rhythmicity during neurodegeneration, and may not be well suited to studying the AD-related circadian deficits [40].”

“Using animal models, abnormalities in sleep, locomotor activity, and body temperature rhythms have been characterized, with reports of decreased nocturnal activity (the equivalent of daytime napping in a nocturnal species) and increased daytime activity (Chauhan et al., 2017).”

“(2013)) or depression (Chauhan et al. (2017)), and improving the e ectiveness of cancer treatments (Chan et al. (2017)). For instance, Haus (2009) demonstrated that the timing of radiation according to host and/or tumour rhythms improves the toxic/therapeutic ratio of the treatment.”