The interplay between chronobiology, neuroinflammation, and the glymphatic system in neurodegenerative diseases

Neurodegenerative diseases are traditionally characterized by the progressive accumulation of misfolded proteins and chronic neuroinflammation. However, emerging evidence indicates that the pathogenesis of these disorders is increasingly recognized to involve the disruption of temporal homeostasis. This conceptual review examines the highly interconnected, bidirectional crosstalk between the molecular circadian clock, glial-mediated neuroimmunity, and the macroscopic glymphatic clearance system. Under physiological conditions, the intrinsic circadian machinery helps maintain microglia in a quiescent, surveillant state and contributes to regulating the perivascular polarization of astrocytic Aquaporin-4 channels, thereby supporting efficient glymphatic fluid dynamics during slow-wave sleep. When this circadian temporal gating is lost due to aging or sleep fragmentation, a self-reinforcing vicious cycle emerges. Molecular clock dysfunction may promote a hyper-reactive microglial phenotype and the sustained release of pro-inflammatory cytokines, which may disrupt astrocytic anchoring complexes. The subsequent depolarization of Aquaporin-4 channels may impair cerebrospinal fluid-interstitial fluid exchange, potentially contributing to the accumulation of neurotoxic aggregates such as Amyloid-β and Tau. Crucially, these accumulated proteins and inflammatory mediators may further feedback to suppress core clock gene expression across the neural network, potentially contributing to disease progression. By synthesizing recent translational and in vivo studies, this perspective suggests that neurodegeneration can also be viewed as neurodegeneration as a network-wide collapse of biological timing in addition to a localized cellular failure. Finally, we highlight the urgent need for targeted chronotherapeutic interventions, specifically emphasizing melatonin as a multi-target resynchronizer with the potential to modulate molecular clocks, reduce microglial reactivity, and support sleep-dependent glymphatic clearance to thereby potentially slow neurodegenerative progression.