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Jiang Y, Zhou X, Wong HY, Ouyang L, FCF Ip, Chau VMN, Lau SF, Wu W, Wong DYK, Seo H, Fu WY, Lai NCH, Chen Y, Chen Y, Tong EPS, Alzheimer’s Disease Neuroimaging Initiative, Mok VCT, Kwok TCY, Mok KY, Shoai M, Lehallier B, Losada PM, O’Brien E, Porter T, Laws SM, Hardy J, Wyss-Coray T, Masters CL, Fu AKY, Ip NY. An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease. Nat Aging (2022). Nature Aging
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VIB-Center for Molecular Neurology
This comprehensive paper goes from clinical observations and genetics to proof of concept in experimental models. One exciting thing about it: It showcases how complicated Alzheimer’s disease is. The authors describe cross talk between endothelial cells and microglia, which has the potential to modulate microglial activity and Aβ deposition.
They also describe genetic variants that can alter this particular interaction and, more importantly, the penetrance of APOE4/4 in AD subjects. This is important in light of available data from my recent preprint and the recent Cell paper from the Goate lab showing that APOE4/4 alone in microglia is perhaps not the most determining factor, implying that there must be other genetic/cellular interactions that play a crucial role.
The cherry on top of the cake is that the effect depends on gender. According to the experimental data shown here, this seems to be dictated by gender differences in the microglia, as the injection of sST2 results in diminished plaque deposition only in female mice.
Regarding the microglial part of the study, I think it is a proof of concept showcasing the multicellular nature of the immune response that occurs in the Alzheimer’s brain. At first glance, infusion of sST2 seems to boost microglia activity with more microglia around plaques, but a closer look shows that they may be unable to adequately interact with amyloid fibrils. It would be interesting to dig deeper into what is the phenotype and surface expressome of these cells, as there we may find key molecular players that mediate the interaction and clearance of amyloid deposits.
View all comments by Renzo MancusoLund University
This study is comprehensive and impressive. If the main results of the study are validated in additional well-characterized, longitudinal cohort studies, sST2 might be an interesting new drug target, especially for females with AD. To me, it would be very interesting to study whether sST2 levels in CSF or plasma are associated with accumulation of Aβ or tau aggregates over time in females with preclinical or prodromal AD.
View all comments by Oskar HanssonNational Institute on Aging
National Institute on Aging
These findings highlight an important endogenous mechanism capable of influencing Aβ clearance among those most at risk of dementia, namely female APOEε4 carriers. Through an integrative and comprehensive multidisciplinary approach, this work led by Nancy Ip’s group shows how lower circulating levels of the sST2 decoy receptor (due to a SNP in its IL1RL1 gene) can promote a microglia activation state, promote microglial clearance of Aβ from the brain, and reduce AD risk among women harboring an APOEε4 allele.
As we noted in our commentary (Duggan and Walker, 2022) published alongside this article in Nature Aging, there is much to be learned by understanding what factors explain the sex- and APOE genotype-specific associations observed by the authors. One possibility is that CSF sST2 levels only influence microglial responses to brain Aβ in individuals who have the combination of high cortical Aβ and suboptimal microglia function—two features more likely to occur in female APOEε4 carriers. Understanding the relationship between sST2 levels and microglia functioning across various disease stages may be informative in this regard and could shed additional light on the potential utility of sST2 as a drug target.
Another outstanding question concerns the mechanistic underpinnings of this receptor’s effects. Does this secreted decoy receptor indeed trigger microglial clearance of Aβ via the canonical signaling cascade for which it is a decoy (i.e., IL-33-ST2L)? In other words, are the low levels of sST2 and associated decreases in Aβ attributed to increased IL-33-ST2L signaling in microglia, which is otherwise inhibited by high levels of sST2? Or, like some other decoy receptors, might sST2 influence microglial clearance of Aβ by other mechanisms independent of its canonical signaling pathway, such as binding directly to Aβ and regulating its uptake (Chakrabarty et al., 2018; Liu et al., 2017)?
Illuminating such mechanistic bases of sST2 may enable the development of therapeutics that boost its protective effects. For example, if the absence of this secreted decoy receptor indeed triggers microglial Aβ clearance by facilitating its canonical signaling cascade (i.e., IL-33-ST2L), then allosteric modulators which enhance IL-33-ST2L binding may augment the beneficial effects associated with lower sST2 levels. Ultimately, Jiang et al.'s findings draw attention to a potentially novel circulating biomarker as well as a molecular target for AD that calls for future investigation.
References:
Duggan MR, Walker KA. Reducing decoys focuses fighting microglia. Nat Aging, July 2022 Nature Aging
Chakrabarty P, Li A, Ladd TB, Strickland MR, Koller EJ, Burgess JD, Funk CC, Cruz PE, Allen M, Yaroshenko M, Wang X, Younkin C, Reddy J, Lohrer B, Mehrke L, Moore BD, Liu X, Ceballos-Diaz C, Rosario AM, Medway C, Janus C, Li HD, Dickson DW, Giasson BI, Price ND, Younkin SG, Ertekin-Taner N, Golde TE. TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer's disease. J Exp Med. 2018 Sep 3;215(9):2247-2264. PubMed.
Liu YL, Chen WT, Lin YY, Lu PH, Hsieh SL, Cheng IH. Amelioration of amyloid-β-induced deficits by DcR3 in an Alzheimer's disease model. Mol Neurodegener. 2017 Apr 24;12(1):30. PubMed.
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