. Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer's Disease. Nat Commun. 2018 Apr 16;9(1):1479. PubMed.


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  1. Given that anti-Aβ immunotherapy induces amyloid phagocytosis and clearance and is being tested in the clinic, the mechanisms that limit natural clearance via this pathway are obviously important. This paper is data-rich and makes a number of interesting and novel claims about the mechanisms limiting amyloid clearance by microglia. In brief, it argues that impaired microglial amyloid phagocytosis in AD is caused by a reduction in neuronal SphK1 that results in less acetylation of COX-2, which in turn leads to deficits in a proresolving lipid mediator, LXA4, a COX-2 product promoted by acetylation of COX-2. LXA4 was previously identified as pro-phagocytic and has been shown by Meideros and others to promote amyloid clearance in 3xAD Tg mice.

    First, this paper offers a new pathway for neuronal regulation of microglia that is provocative and has various implications. For example, it may help explain the anti-inflammatory activity of the second wave of COX-2 induction at 48 hours described by Gilroy and Willoughby (Gilroy et al., 1999). It may help explain how high dose continuous exposure to classical COX inhibitor NSAIDs may increase amyloid accumulation, as was observed previously (Sonnen et al., 2010). This ties in to the issue of NSAID dosing, which is typically intermittent in community epidemiology but chronically high in intervention trials. If chronic COX-2 inhibitors block protective LXA4 production, episodic inhibition with shorter half-life drugs like ibuprofen could avoid LXA4 deficits.

    Because aspirin can also promote acetylated COX-2 and LXA4 generation, this report also raises questions about the potential of aspirin to reduce AD risk. The literature is mixed on this issue but generally suggests that 80mg baby aspirin dosing doesn’t reduce AD risk, while the higher dosing that is required to promote COX-2 acetylation may be protective, notwithstanding some risk for hemorrhage. The report is also interesting in that it highlights the significant potential immunomodulatory protection from an n-6 anti-inflammatory lipid (LXA4) that may help explain the puzzling epidemiology of AD protection with high linoleic acid intake, which is allegedly pro-inflammatory, but not in our experiments with mice. In general, this study suggests an interesting new mechanistic pathway that deserves follow-up and independent efforts to confirm and extend.  


    . Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med. 1999 Jun;5(6):698-701. PubMed.

    . Nonsteroidal anti-inflammatory drugs are associated with increased neuritic plaques. Neurology. 2010 Sep 28;75(13):1203-10. PubMed.

    View all comments by Gregory Cole
  2. The paper from Lee and collaborators is a great example of how much remains yet to discover with respect to nervous system cellular interactions. Microglia, the brain-resident macrophages, are highly tuned to local environmental cues. Yet, they don’t act in isolation. It is evolutionarily advantageous for other neural cell types to signal microglial responses using soluble factors. The present report investigated the ability of neurons to secrete specialized mediators through sphingosine kinase type 1 (Sk1) to signal microglia to re-establish homeostasis. The net positive effect is mitigation of Alzheimer-like pathology. Specifically, the authors posit that neuronal Sk1 promotes lipoxin A4 secretion, which increases microglial Aβ phagocytosis. Interestingly, APP/PS1 mice bearing transgenic neuronal Sk1 present with decreased expression of brain cytokines, including interleukin-10, which we have previously shown to restrict microglial phagocytosis of Aβ. This work nicely illustrates the importance of intercellular communication at the brain-immune interface.

    View all comments by Terrence Town

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  1. Loss of Soothing Lipids in AD Brain Furthers Microglial Mayhem