In Wnt/β-catenin signaling, the β-catenin protein level is deliberately controlled by the assembly of the multiprotein β-catenin destruction complex composed of Axin, adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β), casein kinase 1α (CK1α), and others. Here we provide compelling evidence that formation of the destruction complex is driven by protein liquid–liquid phase separation (LLPS) of Axin. An intrinsically disordered region in Axin plays an important role in driving its LLPS. Phase-separated Axin provides a scaffold for recruiting GSK3β, CK1α, and β-catenin. APC also undergoes LLPS in vitro and enhances the size and dynamics of Axin phase droplets. The LLPS-driven assembly of the destruction complex facilitates β-catenin phosphorylation by GSK3β and is critical for the regulation of β-catenin protein stability and thus Wnt/β-catenin signaling.

Objective: To assess the association between low-density lipoprotein cholesterol (LDL-c) and risk of Alzheimer's disease (AD).Methods: Embase, Pubmed, and Web of Science were searched until June 2019. Standard mean difference (SMD) with 95% confidence intervals (CI) was estimated using random-effects models.Results: Our meta-analysis of 26 studies revealed higher levels of LDL-c in AD than that of non-dementia controls (SMD = 0.35, 95% CI 0.12-0.58, p < 0.01). The meta-regression analysis on confounders showed that age (p < 0.01, Adj R-squared = 92.41%) and cardiovascular disease (p = 0.01, Adj R-squared = 85.21%), but not the body mass index, education, smoking, hypertension and diabetes mellitus, exerted an impact on the relationship between LDL-c and risk of ICH. Further subgroup analysis of age showed LDL-c levels in AD patients aged 60-70 were higher than that of non-dementia (60 ≤ age < 70: SMD = 0.80, 95% CI 0.23-1.37, p < 0.01); but no association between the SMD of AD in LDL-c and age over 70 was noted across the studies (70 ≤ age < 77: SMD = −0.02, 95% CI −0.39∼0.34, p = 9.0; 77 ≤ age < 80: SMD = 0.15, 95% CI −0.17∼0.47, p = 0.35; ≥80: SMD = 0.53, 95% CI −0.04∼1.11, p = 0.07). The concentrations of LDL-c during the quintile interval of 3∼4 were positively associated with AD (121 ≤ concentration < 137: SMD = 0.98, 95% CI 0.13∼1.82, p = 0.02; ≥137: SMD = 0.62, 95% CI 0.18∼1.06, p < 0.01); whereas there was no correlation between AD and LDL-c within the quintile interval of 1∼2 (103.9 ≤ concentration < 112: SMD = 0.08, 95% CI −0.20∼0.35, p = 0.59; 112 ≤ concentration < 121: SMD = −0.26, 95% CI −0.58∼0.06, p = 0.11). Conclusions: Elevated concentration of LDL-c (>121 mg/dl) may be a potential risk factor for AD. This association is strong in patients aged 60-70 years, but vanishes with advancing age.

Background: This meta-analysis aimed to evaluate the relationship between serum uric acid (UA) and the risk of dementia and its subtypes.Methods: Embase, PubMed, and Web of Science were searched from inception to July 2020. Random-effect models were employed to analyze the standard mean difference (SMD) with the corresponding 95% confidence intervals (CI).Results: Twenty-three eligible studies involving 5,575 participants were identified. The overall results showed lower levels of UA in dementia relative to non-dementia controls [SMD = −0.32 (−0.64; −0.01) p = 0.04]. The subgroup analysis of the type of dementia demonstrated a significant association of UA with Alzheimer's disease (AD) [SMD = −0.58 (−1.02; −0.15) p = 0.009] and Parkinson's disease with dementia (PDD) [SMD = −0.33 (−0.52; −0.14) p = 0.001] but not with vascular dementia (VaD). The stratification analysis of the concentrations of UA revealed that the UA quartile 1–2 was negatively correlated with dementia and neurodegenerative subtypes (p &lt; 0.05), whereas a positive correlation of UA quartile 4 with dementia was noted (p = 0.028). Additionally, the meta-regression analysis on confounders showed that not age, body mass index, diabetes mellitus, hypertension, or smoking but education (p = 0.003) exerted an influence of the UA in the risk estimate of dementia.Conclusions: Low concentrations of UA (&lt; 292 μmol/L or 4.91 mg/dL) is a potential risk factor for AD and PDD but not for VaD. The mechanism of different concentrations of the UA in dementia needs to be confirmed through further investigation.

Objective. The objective of this study was to investigate the potential molecular mechanisms of ATPase H+ transporting V1 subunit A (ATP6V1A) underlying Alzheimer’s disease (AD). Methods. Microarray expression data of human temporal cortex samples from the GSE118553 dataset were profiled to screen for differentially expressed genes (DEGs) between AD/control and ATP6V1A-low/high groups. Correlations of coexpression modules with AD and ATP6V1A were assessed by weight gene correlation network analysis (WGCNA). DEGs strongly interacting with ATP6V1A were extracted to construct global regulatory network. Further cross-talking pathways of ATP6V1A were identified by functional enrichment analysis. Diagnostic performance of ATP6V1A in AD prediction was evaluated using area under the curve (AUC) analysis. Results. The mean expression of ATP6V1A was significantly downregulated in AD compared with nondementia controls. A total of 1,364 DEGs were overlapped from AD/control and ATP6V1A-low/high groups. Based on these DEGs, four coexpression modules were predicted by WGCNA. The blue, brown, and turquoise modules were significantly correlated with AD and low ATP6V1A, whose DEGs were enriched in phagosome, oxidative phosphorylation, synaptic vesicle cycle, focal adhesion, and gamma-aminobutyric acidergic (GABAergic) synapse. Global regulatory network was constructed to identify the cross-talking pathways of ATP6V1A, such as synaptic vesicle cycle, phagosome, and oxidative phosphorylation. According to the AUC value of 74.2%, low ATP6V1A expression accurately predicted the occurrence of AD. Conclusions. Our findings highlighted the pleiotropic roles of low ATP6V1A in AD pathogenesis, possibly mediated by synaptic vesicle cycle, phagosome, and oxidative phosphorylation.

Background: The aim of our meta-analysis was to evaluate the association between plasma d-dimer and intracerebral hemorrhage (ICH).Methods: Embase, Pubmed, and Web of Science were searched up to the date of March 19th, 2018, and manual searching was used to extract additional articles. Standard mean difference (SMD) with 95% confidence intervals (CI) was calculated to evaluate d-dimer levels.Results: Thirteen studies including 891 ICH patients and 1,573 healthy controls were included. Our results revealed that higher levels of d-dimer were displayed in ICH patients than those in healthy controls (95% CI= 0.98–2.00, p< 0.001). Subgroup analysis based on continent of Asia and Europe, sample size, as well as age in relation to d-dimer levels between ICH patients and healthy controls did not change the initial observation; whereas no differences of d-dimer levels were found between ICH and controls in America.Conclusions: This meta-analysis revealed that high level of d-dimer is associated with the risk of ICH. Plasma d-dimer is suggested to be a potential biomarker for patients with ICH in Asia and Europe rather than in America. There were no impact of sample size-related differences and age-related diversities on the risk of ICH with respect to d-dimer levels.

The amplitude of Wnt/β-catenin signaling is precisely controlled by the assembly of the cell surface–localized Wnt receptor signalosome and the cytosolic β-catenin destruction complex. How these two distinct complexes are coordinately controlled remains largely unknown. Here, we demonstrated that the signalosome scaffold protein Dishevelled 2 (Dvl2) undergoes liquid–liquid phase separation (LLPS). Dvl2 LLPS is mediated by an intrinsically disordered region and facilitated by components of the signalosome, such as the receptor Fzd5. Assembly of the signalosome is initiated by rapid recruitment of Dvl2 to the membrane, followed by slow and dynamic recruitment of Axin1. Axin LLPS mediates assembly of the β-catenin destruction complex, and Dvl2 attenuates LLPS of Axin. Compared with the destruction complex, Axin partitions into the signalosome at a lower concentration and exhibits a higher mobility. Together, our results revealed that Dvl2 LLPS is crucial for controlling the assembly of the Wnt receptor signalosome and disruption of the phase-separated β-catenin destruction complex.

The intracellular multiprotein complex β-catenin destruction complex plays a key role in Wnt/β-catenin signaling. Wnt stimulation induces the assembly of the receptorassociated signalosome and the inactivation of the destruction complex, leading to β-catenin accumulation and transcriptional activation of the target genes. The core components of the destruction complex include Axin, APC, GSK3β, CK1α and other proteins. Recent studies demonstrated that Axin and APC undergo liquid-liquid phase separation (LLPS), which is critical for their function to regulate Wnt/β-catenin signaling. Here, we discuss the possible roles of LLPS in Wnt/β-catenin signaling and regulation of Axin LLPS by post-translational modifications.

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