Age-related alterations in early and late auditory processing in children with attention-deficit/hyperactivity disorder: Evidence from event-related potentials.

The glymphatic system, first described over a decade ago, facilitates the clearance of interstitial solutes from the brain by driving CSF along perivascular spaces and promoting exchange with interstitial fluid (ISF) []. This process critically depends on aquaporin-4 (AQP4), a water channel highly expressed on astrocytic endfeet surrounding cerebral vasculature, which facilitates efficient water flux necessary for glymphatic function []. Since its initial proposal, accumulating evidence from animal and human studies has supported the existence of glymphatic flow and its relevance to brain homeostasis [, ]. In humans, glymphatic dysfunction has been implicated in Alzheimer’s disease (AD) [, ]. Notably, reductions in glymphatic function not only correlate with disease severity but can also predict subsequent amyloid-β (Aβ) accumulation [], suggesting that impaired glymphatic clearance may actively contribute to AD pathogenesis. Reduced glymphatic flow is thought to impair clearance of extracellular Aβ [], and accumulating Aβ in turn may further compromise glymphatic function [, ], establishing a vicious cycle that accelerates disease progression. While interest in the glymphatic system continues to grow, it remains unclear whether pharmacological enhancement of glymphatic flow is a feasible and effective therapeutic strategy—particularly for tauopathies, where tau accumulation is a critical driver of neuronal loss and cognitive decline. Because glymphatic transport occurs primarily in the extracellular space, it was long assumed to affect only extracellular solutes such as Aβ [, ], leaving its potential influence on intracellular tau pathology uncertain. However, recent studies, including our own, have challenged this view by suggesting that glymphatic dysfunction may alter the extracellular tau pool available for trans-synaptic propagation, thereby indirectly shaping intracellular tau accumulation [–]. These findings raise the possibility that impaired glymphatic flow not only results from but also contributes to tau pathology, pointing toward a bidirectional relationship that has not been fully characterized. To address these unresolved questions, we first examined whether progressive tau accumulation impairs glymphatic flow by visualizing water dynamics in PS19 tauopathy model mice using JJ vicinal coupling proton exchange (JJVCPE) MRI with HO []. We also evaluated age-related glymphatic changes in wild-type mice to distinguish tau-specific effects from normal aging. We further investigated whether pharmacologically enhancing glymphatic function using TGN-073—a blood–brain barrier–permeable small-molecule AQP4 enhancer—could mitigate tau pathology and neurodegeneration in PS19 mice, and validated target specificity in AQP4-deficient mice.