Alzheimer's disease is associated with disruptions in circadian rhythmicity, yet the underlying mechanisms remain only partially understood. Developing insights suggest that astrocytes possess their own intrinsic circadian clocks, influencing multiple functions in brain homeostasis. Given the central role of astrocytes in brain waste clearance, this review investigates how the astrocytic clock mediates brain waste clearance and contributes to Alzheimer's disease pathology. By reviewing recent findings on extracellular clearance, cellular protein homeostasis, cellular detoxification/redox defence and neurotransmitter homeostasis, this review bridges research on astrocytic clock disruption with altered brain waste clearance dynamics. It further highlights the relevance of these alterations to Alzheimer's disease pathology. Interestingly, some clock-gene disruptions are associated with markers suggestive of increased autophagic activity and glymphatic-related gene expression, which may represent a compensatory response to circadian clock alteration. However, whether these changes translate into improved functional clearance in vivo, and whether they meaningfully affect Alzheimer's disease progression, remains uncertain. In contrast, similar clock-gene alterations generally impair blood-brain barrier integrity, glutamate clearance and antioxidant response, decreasing waste clearance capacity. These findings suggest a possible bidirectional relationship, in which some pathways may partially compensate for impairments in others. However, it remains unclear to what extent an imbalance in these pathways contributes to the development and/or progression of Alzheimer's disease. Altogether, the astrocytic circadian clock is positioned as an important regulator of brain waste clearance and warrants future mechanistic and therapeutic investigation.
Retinal ganglion cells (RGCs) exhibit marked heterogeneity in their susceptibility to injury and disease. Intrinsically photosensitive retinal ganglion cells (ipRGCs), a small subset of melanopsin-expressing RGCs involved in non-image-forming visual functions, have emerged as a particularly informative example. In multiple experimental models, ipRGCs show relative resistance to acute insults such as optic nerve injury, excitotoxicity, and mitochondrial dysfuinction. In contrast, functional alterations and degeneration have been reported in aging and in neurodegenerative conditions including Alzheimer's and Parkinson's disease.This apparent discrepancy suggests that ipRGC survival may depend on the nature and duration of the underlying stress. In this review, we summarize current evidence on ipRGC resilience and vulnerability across a range of experimental and pathological contexts. We discuss candidate mechanisms that may contribute to these responses, including sustained activity, calcium handling, metabolic specialization, neurochemical interactions, and gene expression programs. We also consider the role of subtype-specific diversity within the ipRGC population in shaping these outcomes.Finally, we examine the potential of ipRGCs as biomarkers of disease and as a source of insight for neuroprotective strategies. Together, these observations support the view that ipRGC behaviour reflects an interaction between intrinsic cellular properties and the context in which they are engaged.
Sleep disruption is common in Alzheimer's disease (AD). Diphenhydramine (DPH), a first-generation antihistamine with anticholinergic properties, is widely used as an over-the-counter sleep aid. We tested whether chronic DPH treatment alters sleep architecture in 5XFAD and wild-type mice. Female 5XFAD (n=16) and wild-type (WT) littermates (n=14) were implanted with wireless telemetry recording devices to measure electroencephalography (EEG), electromyography (EMG), temperature, and activity continuously. After a 24h baseline recording at 5 months of age, mice received oral DPH (10 mg/kg) or vehicle at ZT0 for one month. After this chronic treatment, sleep was recorded continuously for 48h during ongoing dosing. Sleep was scored as rapid eye movement (REM), non-rapid eye movement (NREM) 1, NREM2, or wake. A survival curve analysis was used to investigate the microarchitecture of sleep phases after chronic diphenhydramine treatment. At baseline, 5XFAD mice had more time in NREM1 than WT controls and had shorter REM and NREM2 bouts. Chronic DPH treatment fragmented NREM2 in both genotypes, reducing long NREM2 bouts. DPH increased total duration of NREM1 and REM during the active phase, which is analogous to daytime drowsiness in humans. DPH did not rescue 5XFAD sleep deficits; instead, DPH treatment exacerbated NREM2 fragmentation. Overall, chronic DPH use degrades sleep quality and increases fragmentation in both WT and AD-model mice, which questions the use of sedating anticholinergics as sleep aids, especially in AD.
Studying the transcriptional changes in the brain following sleep deprivation has provided insight into the molecular mechanisms that differ between sleep and wake. Individual studies are limited in their ability to detect differentially expressed genes due to small sample size. Here we performed a meta-analysis of published brain expression data, totalling 173 microarrays across 245 mice. 498 genes were identified as significantly changing with sleep-deprivation at q < 0.01, 96 of which were previously identified by the original studies. Of the remaining 402 novel candidate sleep genes, 14 were associated with human sleep traits and 3 with sleep phenotypes in knockout mice. Candidate gene validation showed significant upregulation of Rasd1 (Dexras1) following sleep deprivation, and phenotyping of Rasd1 KO mice revealed changes in the amount and distribution of behavioural sleep duration and sleep bout structure. These results provide a greater understanding of the molecular correlates of sleep and provide a resource for the sleep research community.
