Neuroinflammation is associated with several neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). Neuroinflammation provides ...protection in acute situations but results in significant damage to the nervous system if chronic. Overexpression of chemokines within the brain results in the recruitment and activation of glial and peripheral immune cells which can propagate a cascading inflammatory response, resulting in neurodegeneration and the onset of neurodegenerative disorders. Recent work has identified the role of atypical chemokine receptors (ACKRs) in neurodegenerative conditions. ACKRs are seven-transmembrane domain receptors that do not follow canonical G protein signaling, but regulate inflammatory responses by modulating chemokine abundance, location, and availability. This review summarizes what is known about the four ACKRs and three putative ACKRs within the brain, highlighting their known expression and discussing the current understanding of each ACKR in the context of neurodegeneration. The ability of ACKRs to alter levels of chemokines makes them an appealing therapeutic target for neurodegenerative conditions. However, further work is necessary to understand the expression of several ACKRs within the neuroimmune system and the effectiveness of targeted drug therapies in the prevention and treatment of neurodegenerative conditions.
Alzheimer's disease (AD) is the most common cause of dementia and, despite decades of effort, there is no effective treatment. In the last decade, many association studies have identified genetic ...markers that are associated with AD status. Two of these studies suggest that an epistatic interaction between variants rs1049296 in the transferrin (TF) gene and rs1800562 in the homeostatic iron regulator (HFE) gene, commonly known as hemochromatosis, is in genetic association with AD. TF and HFE are involved in the transport and regulation of iron in the brain, and disrupting these processes exacerbates AD pathology through increased neurodegeneration and oxidative stress. However, by using a significantly larger data set from the Alzheimer's Disease Genetics Consortium, we fail to detect an association between TF rs1049296 or HFE rs1800562 with AD risk (TF rs1049296 p = 0.38 and HFE rs1800562 p = 0.40). In addition, logistic regression with an interaction term and a synergy factor analysis both failed to detect epistasis between TF rs1049296 and HFE rs1800562 (SF = 0.94; p = 0.48) in AD cases. Each of these analyses had sufficient statistical power (power > 0.99), suggesting that previously reported associations may be the result of more complex epistatic interactions, genetic heterogeneity, or false-positive associations because of limited sample sizes.
While age and the APOE ε4 allele are major risk factors for Alzheimer's disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of ...age without any clinical symptoms of cognitive decline.
We used over 200 "AD resilient" individuals and an innovative, pedigree-based approach to identify genetic variants that segregate with AD resilience. First, we performed linkage analyses in pedigrees with resilient individuals and a statistical excess of AD deaths. Second, we used whole genome sequences to identify candidate SNPs in significant linkage regions. Third, we replicated SNPs from the linkage peaks that reduced risk for AD in an independent dataset and in a gene-based test. Finally, we experimentally characterized replicated SNPs.
Rs142787485 in RAB10 confers significant protection against AD (p value = 0.0184, odds ratio = 0.5853). Moreover, we replicated this association in an independent series of unrelated individuals (p value = 0.028, odds ratio = 0.69) and used a gene-based test to confirm a role for RAB10 variants in modifying AD risk (p value = 0.002). Experimentally, we demonstrated that knockdown of RAB10 resulted in a significant decrease in Aβ42 (p value = 0.0003) and in the Aβ42/Aβ40 ratio (p value = 0.0001) in neuroblastoma cells. We also found that RAB10 expression is significantly elevated in human AD brains (p value = 0.04).
Our results suggest that RAB10 could be a promising therapeutic target for AD prevention. In addition, our gene discovery approach can be expanded and adapted to other phenotypes, thus serving as a model for future efforts to identify rare variants for AD and other complex human diseases.
A recent genome-wide association study (GWAS) of 59 cerebrospinal fluid (CSF) proteins with a connection to Alzheimer's disease (AD) demonstrated an association between increased levels of chemokine ...ligand 2 (CCL2) with an atypical chemokine receptor chemokine-binding protein 2 variant V41A (ACKR2-V41A; rs2228467). High levels of CCL2 are associated with increased risk of AD development as well as other inflammatory diseases. In this study we characterized the biological function of the ACKR2-V41A receptor compared to the wild type allele by measuring its ligand binding affinity, CCL2 scavenging efficiency, and cell activation sensitivity. We transfected Chinese hamster ovary cells with plasmids carrying wild type ACKR2 (ACKR2-WT) or the mutant ACKR2-V41A receptor. Binding affinity assays showed that ACKR2-V41A has a lower binding affinity for CCL2 and CCL4 than ACKR2-WT. CCL2 scavenging results aligned with binding affinity assays, with ACKR2-V41A cells scavenging CCL2 with a lower efficiency than ACKR2-WT. Cell activation assays also showed that ACKR2-V41A cells had significantly lower receptor upregulation (β-Arrestin-dependent signaling pathway) upon stimulation compared to ACKR2-WT cells. These findings provide molecular and biological mechanistic insights into the GWAS association of ACKR2-V41A with increased levels of CCL2 in CSF and possibly other chemokine ligands. Increased CCL2 levels are associated with accelerated cognitive decline and increased risk of AD. Understanding how this atypical chemokine receptor allele increases serum markers of inflammation could lead to novel therapeutic solutions for AD.
Abstract Recent studies have identified the rs75932628 (R47H) variant in TREM2 as an Alzheimer's disease risk factor with estimated odds ratio ranging from 2.9 to 5.1. The Cache County Memory Study ...is a large, population-based sample designed for the study of memory and aging. We genotyped R47H in 2974 samples (427 cases and 2540 control subjects) from the Cache County study using a custom TaqMan assay. We observed 7 heterozygous cases and 12 heterozygous control subjects with an odds ratio of 3.5 (95% confidence interval, 1.3–8.8; p = 0.0076). The minor allele frequency and population attributable fraction for R47H were 0.0029 and 0.004, respectively. This study replicates the association between R47H and Alzheimer's disease risk in a large, population-based sample, and estimates the population frequency and attributable risk of this rare variant.
The solunar theory proposes that the position of the sun and moon can be used to predict activity rates in fish and game species. Several free and premium services use this theory to provide tables ...predicting optimal dates and times for fishing and hunting success. The efficacy of these services was tested by comparing catch per unit effort (CPUE) in a recreational freshwater trout fishery with daily solunar values and coincidence of fishing trips with peak solunar times. CPUE was also compared to environmental variables including lunar phase, lunar illumination, and wind speed. Values predicted by each of the solunar services were strongly correlated to each other and to lunar phase, however, no significant relationship was found between CPUE and any of the solunar values tested, lunar phase, or lunar illumination. Ambient air temperature showed a positive relationship with CPUE, and was a more effective predictor of fishing success than any of the solunar tables tested.
Article highlights
Solunar calendars that use the lunar phase and the positions of the moon and sunshow no correlation to increased fishing success.
Fishing success showed no correlation to moon phase or percent illumination.
Of all variables tested, ambient air temperature was the only one that showed asignificant correlation to catch per unit effort.
Background
Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. The continuous genetic research done on this disease demonstrates the vast complexity of the genetic architecture. ...The most recent whole‐genome sequence analysis (GWAS)included 1.1 million individuals and identified 38 loci associated with AD status with seven novel loci. However, there is no reliable therapeutics to combat the late stages of AD as of late. The identified rare variants in the RAB10 gene show protective effects against developing AD. This work demonstrates that inhibition of the expression of RAB10 yields better outcomes in terms of the amyloid‐beta ratio and cognition. In addition, we demonstrated that RAB10 modulates the NLRC4 inflammasome complex and their derived products IL‐1‐beta, IL‐18, and TNF‐alpha.
Method
In‐vitro experiments were carried out using human neuroblastoma (N2A) cell lines transfected with a mammalian plasmid to overexpress the APP gene and the immortalized microglia HMC3 cell line. We used the compound reference MLi2 and house compounds HT4253 and HT4403 to inhibit the expression of the RAB10. We used ELISA protocols to test the amyloid‐beta 40 and 42 ratios, IL‐1‐beta, IL‐18, and TNF‐alpha secretion. Western blots immunocytochemistry allowed us to determine the phosphorylation of RAB10 and LRRK2, LAMP1, and ASC. In‐vivo behavioral experiments were done using APP/PS1 mice. Hippocampus tissue was collected to run RNA sequence and total proteomics analysis.
Result
A higher dosage of compound HT4253 and HT4403 inhibits phosphorylation of RAB10 with an IC50 of 82 nM and 63 nM, respectably. The inhibition of RAB10 and LRRK2 activates a higher expression of the LAMP1 protein. The incubation with a high compound dosage improved the secretion of the amyloid‐beta 42/40 ratio. The additional experiments and results will be presented at the conference.
Conclusion
This work provides insights into the protective role of RAB10 against AD and neuroinflammation. RAB10 could be a promising therapeutic target for AD prevention.
Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to ...observe statistically significant associations.
To identify genetic variants associated with AD risk using a nonstatistical approach.
Genetic association study in which rare variants were identified by whole-exome sequencing in unrelated individuals of European ancestry from the Alzheimer's Disease Sequencing Project (ADSP). Data were analyzed between March 2017 and September 2018.
Minor alleles genome-wide and in 95 genes previously associated with AD, AD-related traits, or other dementias were tabulated and filtered for predicted functional impact and occurrence in participants with AD but not controls. Support for several findings was sought in a whole-exome sequencing data set comprising 19 affected relative pairs from Utah high-risk pedigrees and whole-genome sequencing data sets from the ADSP and Alzheimer's Disease Neuroimaging Initiative.
Among 5617 participants with AD (3202 57.0% women; mean SD age, 76.4 9.3 years) and 4594 controls (2719 59.0% women; mean SD age, 86.5 4.5 years), a total of 24 variants with moderate or high functional impact from 19 genes were observed in 10 or more participants with AD but not in controls. These variants included a missense mutation (rs149307620 p.A284T, n = 10) in NOTCH3, a gene in which coding mutations are associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), that was also identified in 1 participant with AD and 1 participant with mild cognitive impairment in the whole genome sequencing data sets. Four participants with AD carried the TREM2 rs104894002 (p.Q33X) high-impact mutation that, in homozygous form, causes Nasu-Hakola disease, a rare disorder characterized by early-onset dementia and multifocal bone cysts, suggesting an intermediate inheritance model for the mutation. Compared with controls, participants with AD had a significantly higher burden of deleterious rare coding variants in dementia-associated genes (2314 vs 3354 cumulative variants, respectively; P = .006).
Different mutations in the same gene or variable dose of a mutation may be associated with result in distinct dementias. These findings suggest that minor differences in the structure or amount of protein may be associated with in different clinical outcomes. Understanding these genotype-phenotype associations may provide further insight into the pathogenic nature of the mutations, as well as offer clues for developing new therapeutic targets.
The original version of this article 1 unfortunately contained a typographical error. The 'Alzheimer's Disease Neuroimaging Initiative' was erroneously included as 'Alzheimer's Disease Neuroimaging ...Initative' in the author list of the article.
Background
Paired Immunoglobulin‐like Type 2 Receptor Alpha (PILRA) recognizes specific O‐glycosylated proteins on various cell types, including microglia. A common missense mutation in PILRA, ...rs1859788, that likely causes the confirmed Alzheimer's disease risk locus at 7q21 is in linkage disequilibrium with synonymous variant rs2405442:T>C. This synonymous variant affects a ramp of rare codons at the beginning of PILRA, which may decrease overall transcriptional efficiency. Since reduced inhibitory signaling in microglia has a protective effect on Alzheimer's disease, we propose that destroying a ramp sequence in PILRA will likewise protect against Alzheimer's disease by reducing the amount of PILRA inhibitory receptor.
Methods
We recently developed an algorithm, ExtRamp, to identify ramp sequences within specific gene sequences. Using ExtRamp, we calculated the relative codon adaptiveness of PILRA using all isoforms in GRCh38. We then calculated the relative codon adaptiveness of PILRA with synonymous variant rs2405442:T>C and found that a ramp sequence is present in the reference isoforms but not the mutant isoforms. We predicted that although the mutant has a more common codon, it would have less overall mRNA expression because it lacks a ramp sequence. We performed biological validation using four sets of three qPCR replicates on the longest isoform to determine the transcriptional efficiency of the mutant versus the reference. We normalized the qPCR output by the number of cells.
Results
Figure 1 shows the relative adaptiveness of the longest PILRA reference isoform and the mutant gene averaged over a nine codon window. The mutant gene has a higher codon adaptiveness at the beginning of the gene sequence, which destroys the predicted ramp sequence. Figure 2 shows that our biological validation using qPCR confirms our prediction that the mutant gene has lower mRNA expression (p‐value = 4.45 × 10−9).
Conclusions
Although higher GC content and more common codons generally increase mRNA levels, the ramp sequence appears to play an integral role in transcriptional efficiency in PILRA. Our results show that synonymous variant rs2405442:T>C directly impacts transcriptional efficiency in PILRA and indicates that synonymous variants should be considered in future association analyses for their causal effects on transcriptional efficiency by modifying ramp sequences.
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