The glymphatic expansion of interstitial space during N3 sleep does more than dilute extracellular proteins; it generates rhythmic shear forces that mechanically destabilize sub‑critical tau oligomers before they become aggregation‑competent. As CSF pulsates through perivascular channels driven by slow delta oscillations, the resulting oscillatory shear stress exceeds the critical force needed to unwind loosely bound β‑sheet interfaces in nascent oligomers, promoting their disassembly into monomers or smaller, non‑toxic species. This mechanical remodeling creates a pool of soluble tau that is both more amenable to glymphatic clearance and better suited for recognition by autophagy receptors that preferentially bind exposed hydrophobic patches. Simultaneously, the same shear stimulus activates mechanosensitive integrin‑FAK signaling in astrocytes and neurons, which phosphorylates ULK1 and accelerates autophagosome formation, thereby coupling extracellular waste removal to intracellular aggregate degradation. In contrast, chronic sleep deprivation reduces interstitial volume, dampens shear amplitude, and allows oligomers to persist long enough to undergo structural consolidation into protease‑resistant seeds that evade both glymphatic efflux and autophagic capture.

Testable predictions

1. In vivo two‑photon imaging of tau‑FRET reporters in mice will show a decrease in oligomer‑specific FRET efficiency during natural N3 sleep that is abolished by AQP4 knockdown or by pharmacologically suppressing slow‑wave activity.
2. Applying oscillatory shear stress (0.5–2 Hz, 0.5–2 Pa) to cultured neurons expressing human tau‑P301S will reduce oligomer levels measured by conformation‑specific antibodies (TOC1, T22) without altering total tau, an effect blocked by inhibiting integrin β1 or FAK.
3. Sleep‑deprived mice will exhibit a higher proportion of detergent‑insoluble tau that co‑sediments with lysosome markers, indicating failed autophagic engagement, whereas shear‑treated wild‑type mice will show increased LC3‑II accumulation and p62 degradation correlating with CSF influx speed measured by intrathecal contrast‑enhanced MRI.
4. Human polysomnography data linked to PET‑derived tau burden will reveal that individuals with reduced slow‑wave amplitude (proxy for lower CSF shear) have a higher ratio of PET‑visible tau to CSF‑soluble tau, even after controlling for total sleep time.

Falsifiability If experimental manipulation of shear stress fails to alter oligomer concentrations or autophagic flux, or if enhancing glymphatic flow without altering interstitial dynamics (e.g., via AQP4 overexpression) does not improve tau clearance, the hypothesis that mechanical shear is a primary driver of nocturnal tau triage would be refuted. Conversely, demonstration that shear alone recapitulates the protective effects of sleep on tau homeostasis would substantiate the model and suggest that therapeutic strategies targeting interstitial mechanics—such as low‑frequency transcranial ultrasound—could mimic sleep’s proteostatic benefits.