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As we age, we experience changes in our nighttime sleep and daytime wakefulness. Individuals afflicted with Alzheimer’s disease (AD) can develop sleep problems even before memory and other cognitive deficits are reported. As the disease progresses and cognitive changes ensue, sleep disturbances become even more debilitating. Thus, it is imperative to gain a better understanding of the relationship between sleep and AD pathogenesis. We postulate a bidirectional relationship between sleep and the neuropathological hallmarks of AD; in particular, the accumulation of amyloid-β (Aβ) and tau. Our research group has shown that extracellular levels of both Aβ and tau fluctuate during the normal sleep−wake cycle. Disturbed sleep and increased wakefulness acutely lead to increased Aβ production and decreased Aβ clearance, whereas Aβ aggregation and deposition is enhanced by chronic increased wakefulness in animal models. Once Aβ accumulates, there is evidence in both mice and humans that this results in disturbed sleep. New findings from our group reveal that acute sleep deprivation increases levels of tau in mouse brain interstitial fluid (ISF) and human cerebrospinal fluid (CSF) and chronic sleep deprivation accelerates the spread of tau protein aggregates in neural networks. Finally, recent evidence also suggests that accumulation of tau aggregates in the brain correlates with decreased nonrapid eye movement (NREM) sleep slow wave activity. In this review, we first provide a brief overview of the AD and sleep literature and then highlight recent advances in the understanding of the relationship between sleep and AD pathogenesis. Importantly, the effects of the bidirectional relationship between the sleep−wake cycle and tau have not been previously discussed in other reviews on this topic. Lastly, we provide possible directions for future studies on the role of sleep in AD.

The sleep-wake cycle regulates interstitial fluid (ISF) and cerebrospinal fluid (CSF) levels of β-amyloid (Aβ) that accumulates in Alzheimer’s disease (AD). Furthermore, chronic sleep deprivation (SD) increases Aβ plaques. However, tau, not Aβ, accumulation appears to drive AD neurodegeneration. We tested whether ISF/CSF tau and tau seeding and spreading were influenced by the sleep-wake cycle and SD. Mouse ISF tau was increased ~90% during normal wakefulness versus sleep and ~100% during SD. Human CSF tau also increased more than 50% during SD. In a tau seeding-and-spreading model, chronic SD increased tau pathology spreading. Chemogenetically driven wakefulness in mice also significantly increased both ISF Aβ and tau. Thus, the sleep-wake cycle regulates ISF tau, and SD increases ISF and CSF tau as well as tau pathology spreading.

Alzheimer's disease (AD) is the most common cause of dementia. The APOE-ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD. The APOE genotype modulates the effect of sleep disruption on AD risk, suggesting a possible link between apoE and sleep in AD pathogenesis, which is relatively unexplored. We hypothesized that apoE modifies Aβ deposition and Aβ plaque-associated tau seeding and spreading in the form of neuritic plaque-tau (NP-tau) pathology in response to chronic sleep deprivation (SD) in an apoE isoform-dependent fashion. To test this hypothesis, we used APPPS1 mice expressing human APOE-ε3 or -ε4 with or without AD-tau injection. We found that SD in APPPS1 mice significantly increased Aβ deposition and peri-plaque NP-tau pathology in the presence of APOE4 but not APOE3. SD in APPPS1 mice significantly decreased microglial clustering around plaques and aquaporin-4 (AQP4) polarization around blood vessels in the presence of APOE4 but not APOE3. We also found that sleep-deprived APPPS1:E4 mice injected with AD-tau had significantly altered sleep behaviors compared with APPPS1:E3 mice. These findings suggest that the APOE-ε4 genotype is a critical modifier in the development of AD pathology in response to SD.

Alzheimer’s disease (AD) is the leading cause of dementia. The relationship between AD and sleep dysfunction has received increased attention over the past decade. The use of genetically engineered mouse models with enhanced production of amyloid beta (Aβ) or hyperphosphorylated tau has played a critical role in the understanding of the pathophysiology of AD. However, their revelations regarding the progression of sleep impairment in AD have been highly dependent on the mouse model used and the specific techniques employed to examine sleep. Here, we discuss the sleep disturbances and general pathology of 15 mouse models of AD. Sleep disturbances covered in this review include changes to NREM and REM sleep duration, bout lengths, bout counts and power spectra. Our aim is to describe in detail the severity and chronology of sleep disturbances within individual mouse models of AD, as well as reveal broader trends of sleep deterioration that are shared among most models. This review also explores a variety of potential mechanisms relating Aβ accumulation and tau neurofibrillary tangles to the progressive deterioration of sleep observed in AD. Lastly, this review offers perspective on how study design might impact our current understanding of sleep disturbances in AD and provides strategies for future research.

People with diabetes are more likely to experience sleep disturbance than those without. Sleep disturbance can cause daytime sleepiness in diabetic patients, which may impair their daytime performance or even lead to workplace injuries. Therefore, restoring the normal sleep-wake cycle is critical for diabetic patients who experience daytime sleepiness. Previous data on a diabetic mouse model, the mice, have demonstrated that the total sleep time and sleep fragmentation are increased and the daily rhythm of the sleep-wake cycle is attenuated. Accumulating evidence has shown that active time-restricted feeding (ATRF), in which the timing of food availability is restricted to the active-phase, is beneficial to metabolic health. However, it is unknown whether ATRF restores the normal sleep-wake cycle in diabetes. To test that, we used a non-invasive piezoelectric system to monitor the sleep-wake profile in the mice with feeding (ALF) as a baseline and then followed with ATRF. The results showed that at baseline, mice exhibited abnormal sleep-wake patterns: the sleep time percent during the light-phase was decreased, while during the dark-phase it was increased with unusual cycling compared to control mice. In addition, the sleep bout length during both the light-phase and the full 24-h period was shortened in mice. Analysis of the sleep-wake circadian rhythm showed that ATRF effectively restored the circadian but suppressed the ultradian oscillations of the sleep-wake cycle in the mice. In conclusion, ATRF may serve as a novel strategy for treating diabetes-induced irregularity of the sleep-wake cycle.

Most published sleep studies use three species: human, house mouse, or Norway rat. The degree to which data from these species captures variability in mammalian sleep remains unclear. To gain insight into mammalian sleep diversity, we examined sleep architecture in the spiny basal murid rodent Acomys cahirinus . First, we used a piezoelectric system validated for Mus musculus to monitor sleep in both species. We also included wild M. musculus to control for alterations generated by laboratory-reared conditions for M. musculus . Using this comparative framework, we found that A. cahirinus , lab M. musculus, and wild M. musculus were primarily nocturnal, but exhibited distinct behavioral patterns. Although the activity of A. cahirinus increased sharply at dark onset, it decreased sharply just two hours later under group and individual housing conditions. To further characterize sleep patterns and sleep-related variables, we set up EEG/EMG and video recordings and found that A. cahirinus sleep significantly more than M. musculus , exhibit nearly three times more REM, and sleep almost exclusively with their eyes open. The observed differences in A. cahirinus sleep architecture raise questions about the evolutionary drivers of sleep behavior .

Corpora amylacea (CA) and their murine analogs, periodic acid Schiff (PAS) granules, are age-related, carbohydrate-rich structures that serve as waste repositories for aggregated proteins, damaged cellular organelles, and other cellular debris. The structure, morphology, and suspected functions of CA in the brain imply disease relevance. Despite this, the link between CA and age-related neurodegenerative diseases, particularly Alzheimer’s disease (AD), remains poorly defined. We performed a neuropathological analysis of mouse PAS granules and human CA and correlated these findings with AD progression. Increased PAS granule density was observed in symptomatic tau transgenic mice and APOE knock-in mice. Using a cohort of postmortem AD brain samples, we examined CA in cognitively normal and dementia patients across Braak stages with varying APOE status. We identified a Braak-stage dependent bimodal distribution of CA in the dentate gyrus, with CA accumulating and peaking by Braak stages II–III, then steadily declining with increasing tau burden. Refined analysis revealed an association of CA levels with both cognition and APOE status. Finally, tau was detected in whole CA present in human patient cerebrospinal fluid, highlighting CA-tau as a plausible prodromal AD biomarker. Our study connects hallmarks of the aging brain with the emergence of AD pathology and suggests that CA may act as a compensatory factor that becomes depleted with advancing tau burden.

Sleep disturbances are common maladies associated with human age. Sleep duration is decreased, sleep fragmentation is increased, and the timing of sleep onset and sleep offset is earlier. These disturbances have been associated with several neurodegenerative diseases. Mouse models for human sleep disturbances can be powerful due to the accessibility to neuroscientific and genetic approaches, but these are hampered by the fact that most mouse models employed in sleep research have spontaneous mutations in the biosynthetic pathway(s) regulating the rhythmic production of the pineal hormone melatonin, which has been implicated in human sleep. The present study employed a non-invasive piezoelectric measure of sleep wake cycles in young, middle-aged and old CBA mice, a strain capable of melatonin biosynthesis, to investigate naturally-occurring changes in sleep and circadian parameters as the result of aging. The results indicate that young mice sleep less than do middle-aged or aged mice, especially during the night, while the timing of activity onset and acrophase is delayed in aged mice compared to younger mice. These data point to an effect of aging on the quality and timing of sleep in these mice but also that there are fundamental differences between control of sleep in humans and in laboratory mice.

Sleep disruption is a characteristic of Alzheimer's disease (AD) that may exacerbate disease progression. This study tested whether a dual orexin receptor antagonist (DORA) would enhance sleep and attenuate neuropathology, neuroinflammation, and cognitive deficits in an AD-relevant mouse model, 5XFAD. Wild-type (C57Bl6/SJL) and 5XFAD mice received chronic treatment with vehicle or DORA-22. Piezoelectric recordings monitored sleep and spatial memory was assessed via spontaneous Y-maze alternations. Aβ plaques, Aβ levels, and neuroinflammatory markers were measured by immunohistochemistry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction, respectively. In 5XFAD mice, DORA-22 significantly increased light-phase sleep without reducing Aβ levels, plaque density, or neuroinflammation. Effects of DORA-22 on cognitive deficits could not be determined because the 5XFAD mice did not exhibit deficits. These findings suggest that DORAs may improve sleep in AD patients. Further investigations should optimize the dose and duration of DORA-22 treatment and explore additional AD-relevant animal models and cognitive tests. •Daily DORA-22 treatment at light onset for 5 weeks increased sleep in 5XFAD mice.•DORA-22 mainly increased sleep during the light (inactive) phase.•Chronic DORA-22 treatment did not affect cortical amyloid β levels or plaques.•Chronic DORA-22 treatment did not alter cortical neuroinflammation.

Extracellular deposition of amyloid-β as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles are two of the characteristic hallmarks of Alzheimer’s disease 1 , 2 . The regional progression of brain atrophy in Alzheimer’s disease highly correlates with tau accumulation but not amyloid deposition 3 – 5 , and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. So far, little is known about the extent or role of the adaptive immune response and its interaction with the innate immune response in the presence of amyloid-β or tau pathology 6 . Here we systematically compared the immunological milieux in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not those with amyloid deposition developed a unique innate and adaptive immune response and that depletion of microglia or T cells blocked tau-mediated neurodegeneration. Numbers of T cells, especially those of cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the Alzheimer’s disease brain. T cell numbers correlated with the extent of neuronal loss, and the cells dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of interferon-γ and PDCD1 signalling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy- and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in Alzheimer’s disease and primary tauopathies. A study finds T cells in areas of tau, not amyloid, pathology in Alzheimer’s disease brain and mouse models, with their presence correlating with neuronal loss and their depletion, or that of microglia, preventing neurodegeneration and cognitive decline.