Long-Term High-Fat Diet Impairs AQP4-Mediated Glymphatic Clearance of Amyloid Beta

Jul 3, 2024Molecular neurobiology

Long-Term High-Fat Diet May Reduce Brain Waste Clearance of Amyloid Beta by Water Channels

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Abstract

Long-term high-fat diet (HFD) is associated with decreased clearance of amyloid beta (Aβ) in the brain.

HFD-fed mice showed reduced Aβ clearance after injection into the hippocampus.
Glymphatic function was decreased in HFD-fed mice, as indicated by reduced uptake of fluorescent tracers.
Disruption of aquaporin-4 (AQP4) polarization in the cortex was observed in long-term HFD-fed mice.
AQP4 polarization index was positively correlated with glymphatic clearance activity.
Inhibition of AQP4 with TGN-020 worsened Aβ clearance disruption, while enhancement with TGN-073 improved it.

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As a risk factor for Alzheimer's disease (AD), studies have demonstrated that long-term high-fat diet (HFD) could accelerate the deposition of amyloid beta (Aβ) in the brain. The glymphatic system plays a critical role in Aβ clearance from the brain. However, studies investigating the effects of long-term HFD on glymphatic function have reported paradoxical outcomes, and whether glymphatic dysfunction is involved in the disturbance of Aβ clearance in long-term HFD-fed mice has not been determined. In the present study, we injected fluorescently labeled Aβ into the hippocampus and found that Aβ clearance was decreased in HFD-fed mice. We found that long-term HFD-fed mice had decreased glymphatic function by injecting fluorescent tracers into the cisterna magna and corpus striatum. In long-term HFD-fed mice, aquaporin-4 (AQP4) polarization in the cortex was disrupted, and glymphatic clearance activity was positively correlated with the AQP4 polarization index. In HFD-fed mice, the disturbance of Aβ clearance from the hippocampus was exacerbated by TGN-020, a specific inhibitor of AQP4, whereas TGN-073, an enhancer of AQP4, ameliorated it. These findings suggest that long-term HFD disrupts Aβ clearance by inhibiting AQP4-mediated glymphatic function. The underlying mechanism may involve the disruption of AQP4 polarization.

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Long-Term High-Fat Diet Impairs AQP4-Mediated Glymphatic Clearance of Amyloid Beta

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