Nonetheless, it is unclear what regulatory mechanisms underlie sST2 dysregulation and whether sST2 plays a pathological role in AD. Notably, recent evidence shows that sST2 levels are also elevated in the blood of individuals with mild cognitive impairment (MCI) or AD 24, 32. Altered sST2 level in plasma is a biomarker of several inflammatory and cardiac diseases 28, 29, 30, 31. Meanwhile, sST2 acts as a decoy receptor of IL-33 and inhibits IL-33–ST2 signaling 26, 27. ST2L is expressed by microglia in the brain 23, and activation of IL-33–ST2 signaling decreases Aβ accumulation via enhanced microglial Aβ-clearance capacity in transgenic mouse models of amyloidosis 24, 25.
In particular, sST2 is a secreted isoform of the interleukin-33 (IL-33) receptor ST2L (full-length ST2) that is produced by alternative promoter activation 22 (Extended Data Fig. Other secreted proteins that contribute to AD pathogenesis include soluble cytokine receptors comprising the ectodomains of membrane-bound cytokine receptors, which function as decoy receptors to attenuate cytokine-mediated signaling 20, 21. Moreover, the soluble form of a full-length VCAM1 protein in endothelial cells, sVCAM1, is increased in the plasma and CSF of individuals with AD 17, 18 this is suggested to mediate reduced hippocampal neurogenesis and a pro-inflammatory response by microglia during aging 19. For example, soluble TREM2 protein (sTREM2) level is increased in the cerebrospinal fluid (CSF) of individuals with AD 12, 13, 14, and injection of sTREM2 in transgenic mouse models of amyloidosis alleviates Aβ accumulation by enhancing the interaction between microglia and Aβ and subsequent Aβ phagocytosis 15, 16. Recent studies show that, besides genetic factors, changes in secreted proteins in the brain milieu and/or circulatory system may also disrupt microglial activities and contribute to AD pathogenesis 10, 11. This suggests that microglial dysfunction plays an essential causative role in AD. In particular, APOE-ε4, the strongest known risk factor for sporadic AD after chronological age 3, affects Aβ accumulation in AD 6, 7 through regulating the clustering of microglia around Aβ and the subsequent degradation of Aβ plaques 4, 8, 9. While the pathophysiological mechanisms underlying AD remain unclear, genome-wide association studies (GWASs) reveal more than 40 AD-associated genes linked with microglial functions (for example, APOE, TREM2, BIN1 and CD33), suggesting that microglia play a key role in AD pathogenesis 3, 4, 5. Its pathological hallmarks include the extracellular accumulation of Aβ peptides, which form Aβ plaques, and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein (P-tau) 2. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.ĪD is the most common neurodegenerative disease and a leading cause of mortality in older people 1. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622/sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E ( APOE)-ε4 genotype the association is stronger in Chinese than in European-descent populations. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD.
Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Nature Aging volume 2, pages 616–634 ( 2022) Cite this articleĬhanges in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear.
Alzheimer’s Disease Neuroimaging Initiative,.An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease
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