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BackgroundInsufficient clearance of soluble oligomeric amyloid-β peptide (oAβ) in the central nervous system leads to the synaptic and memory deficits in Alzheimer's disease (AD). Previously we have identified scavenger receptor class A (SR-A) of microglia mediates oligomeric amyloid-β peptide (oAβ) internalization by siRNA approach. SR-A is a member of cysteine-rich domain (SRCR) superfamily which contains proteins actively modulating the innate immunity and host defense, however the functions of the SRCR domain remain unclear. Whether the SRCR domain of SR-AI modulates the receptor surface targeting and ligand internalization was investigated by expressing truncated SR-A variants in COS-7 cells. Surface targeting of SR-A variants was examined by live immunostaining and surface biotinylation assays. Transfected COS-7 cells were incubated with fluorescent oAβ and acetylated LDL (AcLDL) to assess their ligand-internalization capabilities.ResultGenetic ablation of SR-A attenuated the internalization of oAβ and AcLDL by microglia. Half of oAβ-containing endocytic vesicles was SR-A positive in both microglia and macrophages. Clathrin and dynamin in SR-AI-mediated oAβ internalization were involved. The SRCR domain of SR-AI is encoded by exons 10 and 11. SR-A variants with truncated exon 11 were intracellularly retained, whereas SR-A variants with further truncations into exon 10 were surface-targeted. The fusion of exon 11 to the surface-targeted SR-A variant lacking the SRCR domain resulted in the intracellular retention and the co-immunoprecipitation of Bip chaperon of the endoplasmic reticulum. Surface-targeted variants were N-glycosylated, whereas intracellularly-retained variants retained in high-mannose states. In addition to the collagenous domain, the SRCR domain is a functional binding domain for oAβ and AcLDL. Our data suggest that inefficient folding of SR-AI variants with truncated SRCR domain was recognized by the endoplasmic reticulum associated degradation which leads to the immature N- glycosylation and intracellular retention.ConclusionThe novel functions of the SRCR domain on regulating the efficacy of receptor trafficking and ligand binding may lead to possible approaches on modulating the innate immunity in Alzheimer’s disease and atherosclerosis.

Objectives: The association between tinnitus and anxiety disorder remains debated. We used a retrospective cohort study to investigate the relationship between anxiety disorder and tinnitus, aiming to decipher possible risk factors for tinnitus in patients with anxiety disorder. Method: Data on a total of 7,525 patients with anxiety disorder and 15,050 patients without (comparison cohort) were extracted from the Longitudinal Health Insurance Database 2005 in Taiwan. The Kaplan-Meier estimator with the log rank test and the Cox proportional-hazard regression model were used to compare the incidence of tinnitus in both groups and to identify risk factors that predicted tinnitus. Results: After adjusting for related covariates, the hazard ratio for the development of tinnitus during the follow-up period was 3.54 (95% confidence interval: 3.11-4.02, P < .001) for anxiety disorder cohort relative to comparison cohort. Age ≧ 60 years, female sex, hypertension, and hyperlipidemia were statistically significant predictive risk factors of tinnitus in patients with anxiety disorder. Conclusion: A significant increase in the lifetime incidence of tinnitus was exhibited in patients with anxiety disorder. Elderly subjects, female sex, hypertension, and hyperlipidemia were risk factors. Clinicians should be alert to the possibility of tinnitus in subjects with anxiety disorder.

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