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Published on: October 30, 2018
Cellular basis of medium flow-mediated reduction of Aβ neurotoxicity in cultured neurons
Yoshiki Yagi1, Sora Oda1, Hitoshi Tatsumi1
1Department of Applied Bioscience, Kanazawa Institute of Technology, Hakusan-shi, Ishikawa 924-0838, Japan.
Abstract:
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.
Insights
Medium flow reduces Alzheimer's disease neurotoxicity by decreasing amyloid-beta (Aβ1-42) particle binding to neurons. This mechanism involves altered cell-surface glycosylation, offering potential therapeutic insights for neurodegenerative disorders.
Area of Science:
- Neuroscience
- Biophysics
Background:
- Alzheimer's disease (AD) involves toxic amyloid-beta (Aβ1-42) accumulation in the brain.
- Cilia-generated fluid flow was observed to reduce Aβ1-42 neurotoxicity in brain explants, but mechanisms were unknown.
Purpose of the Study:
- To investigate the mechanisms by which medium flow mitigates Aβ1-42 neurotoxicity.
- To explore the role of extracellular particles (EPs) and cell-surface interactions in Aβ1-42 toxicity under flow conditions.
Main Methods:
- Utilized explant brain cultures with beating ependymal cilia and introduced Aβ1-42.
- Analyzed Aβ1-42-containing putative EV-related EPs under varying flow conditions and inhibited EV release/endocytosis.
- Assessed neuronal binding of EPs and cell-surface glycosylation using microscopy and staining.
Main Results:
- Medium flow significantly reduced the binding and duration of Aβ1-42-containing EPs on neurons.
- Inhibition of EV release and endocytosis decreased intracellular Aβ1-42 and neuronal toxicity.
- Enhanced cell-surface glycan labeling was observed in damaged neurons on the non-ciliated side.
Conclusions:
- Shear stress from medium flow reduces neuronal accumulation of toxic Aβ1-42-containing EPs.
- Modulation of cell-surface glycosylation is a likely mechanism by which flow alleviates Aβ1-42 neurotoxicity.
- Findings suggest potential therapeutic strategies targeting fluid dynamics and cell-surface interactions in AD.
