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Review
. 2025 Aug 5;26(15):7552.
doi: 10.3390/ijms26157552.

The Therapeutic Potential of Glymphatic System Activity to Reduce the Pathogenic Accumulation of Cytotoxic Proteins in Alzheimer's Disease

Kamila Kopeć  1 , Dariusz Koziorowski  1 , Stanisław Szlufik  1
Affiliations
Review

The Therapeutic Potential of Glymphatic System Activity to Reduce the Pathogenic Accumulation of Cytotoxic Proteins in Alzheimer's Disease

Kamila Kopeć et al. Int J Mol Sci. .

Abstract

Neurodegenerative disorders, including Alzheimer's disease (AD), are a growing problem in aging society. The amyloid cascade hypothesis has recently been questioned, and therapies based on it have not yielded the expected results. However, the role of amyloid-β (Aβ) in AD pathogenesis cannot be rejected. It appears that some of the key players in the pathogenesis of the disease are the soluble amyloid-β oligomers. Soluble amyloid-β oligomers have neurotoxic effects by disrupting intracellular Ca2+ homeostasis and impairing mitochondrial function. The glymphatic system is an important pathway for the removal of soluble amyloid forms from the brain. The decline in the activity of this system is observed in aging brains, which is correlated with the occurrence of Alzheimer's disease, primarily among the elderly population. Therefore, the question arises as to whether the glymphatic system could be another potential target for therapeutic interventions in Alzheimer's disease. In this regard, it is imperative to pay attention to the factors that contribute to the pathogenesis of Alzheimer's disease and also impact the glymphatic system, such as sleep, physical activity, alcohol consumption, and supplementation with polyunsaturated fatty acids. The question remains whether the glymphatic system will become the key to treating Alzheimer's disease.

Keywords: Alzheimer’s disease; amyloid-β oligomers; aquaporin-4; glymphatic system; neurodegeneration; neuroinflammation.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The multidirectional mechanism of AβO toxicity. “Created in BioRender. Kopeć, K. (2025) https://BioRender.com/3uykp0b (accessed on 7 July 2025)”.
Figure 2
Figure 2
A schematic representation of the glymphatic system. “Created in BioRender. Kopeć, K. (2025) https://BioRender.com/ilhkcp2 (accessed on 7 July 2025)”.
Figure 3
Figure 3
Potential factors influencing AD pathogenesis and glymphatic system activity. “Created in BioRender. Kopeć, K. (2025) https://BioRender.com/nz44w9n (accessed on 7 July 2025)”.
See this image and copyright information in PMC

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