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Cyclooxygenase-2 is critical for the propagation of β-amyloid protein and reducing the glycosylation of tau in Alzheimer’s disease

Cellular & Molecular Immunology volume 16, pages 892–894 (2019)Cite this article

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Alzheimer’s disease (AD) is generally believed to be caused by the production of β-amyloid protein (Aβ), and hyperphosphorylation of tau, which are deposited in β-amyloid plaques (APs) and neurofibrillary tangles (NFTs), respectively. However, the inherent reasons for their propagation and deposition remain unknown. In light of our prior works, magnesium (Mg2+) deficiency is critical for the onset of AD.1 In addition, the restoration of Mg2+ in the brain reduces neuroinflammation by suppressing the expression of interleukin (IL)-1β,1 which decreases Aβ overload in an APH-1α/1β-dependent mechanism.2 In this regard, inflammation is the target of Mg2+ in the treatment of AD. In addition to IL-1β, a powerful inflammatory inducer, cyclooxygenase-2 (COX-2), has also been reported to be inhibited by the addition of Mg2+.3 We thereby extended our prior works to COX-2. Analyses of the underlying mechanisms elucidated the role of COX-2 in spreading Aβ deposits in APs to the cerebellum. This was probably caused by the formation of hetero-oligomers between COX-2 and Aβ, which have been shown to accelerate the aggregation and deposition of Aβ in APs.4 Moreover, the induction of COX-2 decreased the glycosylation of tau, which has been shown to result in the phosphorylation of tau in different animal models. In this scenario, the status of tau phosphorylation is critical for the development and progression of AD.5 Therefore, COX-2 appears to be a potential therapeutic target for AD.

Recently, the concept of the prion-like transmission of pathogenic proteins in AD was experimentally validated, and this concept has been gradually accepted by many neuroscientists. Goudsmit et al. proposed the hypothesis of “transmissibility of amyloidosis” as early as the 1980s. Jucker’s team further injected brain homogenates from patients with AD containing Aβ into APP transgenic mice and demonstrated that brain homogenate injection can significantly increase the amyloid metabolism of APP in the brains of transgenic mice.6 In addition, some studies have shown that prion proteins can also bind to Aβ as a complex to promote the transmission of Aβ in AD brains.7 More importantly, Aβ monomers also have molecular transmissibility in APP transgenic mice, and exosomes may mediate the transmission of Aβ monomers between cells and tissues.8 Based on the above findings, Soto et al. noted that the molecular mechanism of Aβ transmission is very similar to that of prion protein and further proposed that misfolded proteins have the inherent capability of prion-like transmission.9 The prion-like “seed effect” theory10 not only reasonably explains the physical and chemical characteristics of Aβ monomers during transformation to oligomers and fibrous aggregates but also provides theoretical support for the transmission of Aβ during the occurrence and development of AD.

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Acknowledgements

This work was supported, in part or in whole, by the National Natural Science Foundation of China (CN) (81771167, 81870840 and 81901116) and the Fundamental Research Funds for the Central Universities, China (N172008008 and N172004005).

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  1. College of Life and Health Sciences, Northeastern University, 110819, Shenyang, PR China

    Pei-Pei Guan, Yan-Hui Zou & Pu Wang

  2. Institute of Health Science, China Medical University, 110122, Shengyang, PR China

    Xin Yu

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Correspondence to Pu Wang.

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Guan, PP., Yu, X., Zou, YH. et al. Cyclooxygenase-2 is critical for the propagation of β-amyloid protein and reducing the glycosylation of tau in Alzheimer’s disease. Cell Mol Immunol 16, 892–894 (2019). https://doi.org/10.1038/s41423-019-0294-1

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