Cellular basis of medium flow-mediated reduction of Aβ neurotoxicity in cultured neurons.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by elevated concentrations of amyloid β1-42 (Aβ1-42) in the brain, where it exerts neurotoxic effects. A recent study demonstrated that medium flow at approximately 10 μm/s reduces Aβ1-42 neurotoxicity in explant brain cultures containing neurons and beating ependymal cilia; however, the underlying mechanisms remain unclear. Neurons migrating from the explant and located within 300 μm of the beating cilia were exposed to cilia-generated medium flow, allowing analysis of Aβ1-42 toxicity under fluid flow conditions. Aβ1-42-containing putative EV-related extracellular particles (putative EV-related Eps), with diameters of 100-400 nm were detected in the culture medium and exhibited neurotoxic effects. Pharmacological inhibition of EV release and endocytosis reduced intracellular accumulation of Aβ1-42 and attenuated neuronal toxicity. Under medium flow, fewer putative EV-related EPs bound to neurons, and their binding duration was significantly shortened. Rhodamine-conjugated concanavalin A staining revealed enhanced cell-surface glycan labeling in damaged neurons on the non-ciliated side compared with neurons on the ciliated side. These results suggest that shear stress reduces neuronal accumulation of Aβ1-42-containing putative EV-related EPs, likely through modulation of cell-surface glycosylation composition.