Sleep may protect the brain from AD: Two main proteins accumulate in the brain in Alzheimer's disease (AD), β-amyloid (Aβ) and tau. Aβ appears to instigate AD, but tau appears to drive brain damage and cognitive decline. Sleep deprivation is known to increase Aβ acutely and chronically. Now, Holth et al. show that chronic sleep deprivation strongly increases tau acutely over hours and also drives tau pathology spreading in the brains of mice and humans (see the Perspective by Noble and Spires-Jones). Thus, sleep appears to have a direct protective effect on a key protein that drives AD pathology. Science , this issue p. 880 ; see also p. 813

Sleep loss is associated with cognitive decline in the aging population and is a risk factor for Alzheimer’s disease (AD). Considering the crucial role of immunomodulating genes such as that encoding the triggering receptor expressed on myeloid cells type 2 (TREM2) in removing pathogenic amyloid-β (Aβ) plaques and regulating neurodegeneration in the brain, our aim was to investigate whether and how sleep loss influences microglial function in mice. We chronically sleep-deprived wild-type mice and the 5xFAD mouse model of cerebral amyloidosis, expressing either the humanized TREM2 common variant, the loss-of-function R47H AD-associated risk variant, or without TREM2 expression. Sleep deprivation not only enhanced TREM2-dependent Aβ plaque deposition compared with 5xFAD mice with normal sleeping patterns but also induced microglial reactivity that was independent of the presence of parenchymal Aβ plaques. We investigated lysosomal morphology using transmission electron microscopy and found abnormalities particularly in mice without Aβ plaques and also observed lysosomal maturation impairments in a TREM2-dependent manner in both microglia and neurons, suggesting that changes in sleep modified neuro-immune cross-talk. Unbiased transcriptome and proteome profiling provided mechanistic insights into functional pathways triggered by sleep deprivation that were unique to TREM2 and Aβ pathology and that converged on metabolic dyshomeostasis. Our findings highlight that sleep deprivation directly affects microglial reactivity, for which TREM2 is required, by altering the metabolic ability to cope with the energy demands of prolonged wakefulness, leading to further Aβ deposition, and underlines the importance of sleep modulation as a promising future therapeutic approach.

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.

Introduction: 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. Methods: 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. Results: 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. Discussion: 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.

Background: 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. Purpose and method: 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. Results: 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. Conclusion: 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.

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 rodentAcomys cahirinus. First, we used a piezoelectric system validated forMus musculusto monitor sleep in both species. We also included wildM. musculusto control for alterations generated by laboratory-reared conditions forM. musculus. Using this comparative framework, we found thatA. cahirinus, labM. musculus,and wildM. musculuswere primarily nocturnal, but exhibited distinct behavioral patterns. Although the activity ofA. cahirinusincreased 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 thatA. cahirinussleep significantly more thanM. musculus, exhibit nearly three times more REM, and sleep almost exclusively with their eyes open. The observed differences inA. cahirinussleep architecture raise questions about the evolutionary drivers of sleep behavior.