👤 Thomas Flynn

Alzheimer's disease features early a pathology in the locus coeruleus (LC), yet how sex and life experience shape LC vulnerability remains poorly understood. We expressed pseudophosphorylated human tau (htauE14) in LC neurons of TH-Cre rats and exposed both sexes to early- or late-life enrichment or stress. Behavioral, histological, protein, and hippocampal single-nucleus RNA sequencing (snRNA-seq) analyses were performed. LC-targeted htauE14 impaired learning and increased anxiety-like behavior. Early enrichment reduced htauE14 spread and LC microglia activation, elevated hippocampal brain-derived neurotrophic factor (BDNF), and improved olfactory learning in males. Late enrichment alleviated anxiety and enhanced spatial memory, whereas late stress exacerbated LC degeneration. Hippocampal snRNA-seq revealed sex- and cell type-specific transcriptional responses, with htauE14 preferentially engaging metabolic and synaptic pathways in females, effects amplified by early stress but stabilized by early enrichment. Late-life experiences primarily recruited homeostatic regulatory programs. Sex and developmental history critically shape early LC tau-related vulnerability. Show less

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion ( Show less

Mounting evidence has shown that CETP has important physiological roles in adapting to chronic nutrient excess, specifically, to protect against diet-induced insulin resistance. However, the underlying mechanisms for the protective roles of CETP in metabolism are not yet clear. Mice naturally lack CETP expression. We used transgenic mice with a human CETP minigene (huCETP) controlled by its natural flanking region to further understand CETP-related physiology in response to obesity. Female huCETP mice and their wild-type littermates were fed a high-fat diet for 6 months. Blood lipid profile and liver lipid metabolism were studied. Insulin sensitivity was analyzed with euglycemic-hyperinsulinemic clamp studies combined with Show less

Interleukin-6 (IL-6) is a cytokine implicated in proinflammatory as well as regenerative processes and acts via receptor complexes consisting of the ubiquitously expressed, signal-transducing receptor gp130 and the IL-6 receptor (IL-6R). The IL-6R is expressed only on hepatocytes and subsets of leukocytes, where it mediates specificity of the receptor complex to IL-6 as the subunit gp130 is shared with all other members of the IL-6 cytokine family such as IL-11 or IL-27. The amount of IL-6R at the cell surface thus determines the responsiveness of the cell to the cytokine and might therefore be decisive in the development of inflammatory disorders. However, how the expression levels of IL-6R and gp130 at the cell surface are controlled is largely unknown. Here, we show that IL-6R and gp130 are constitutively internalized independent of IL-6. This process depends on dynamin and clathrin and is temporally controlled by motifs within the intracellular region of gp130 and IL-6R. IL-6 binding and internalization of the receptors is a prerequisite for activation of the Jak/STAT signaling cascade. Targeting of gp130, but not of the IL-6R, to the lysosome for degradation depends on stimulation with IL-6. Furthermore, we show that after internalization and activation of signaling, both the IL-6R and gp130 are recycled back to the cell surface, a process that is enhanced by IL-6. These data reveal an important function of IL-6 beyond the pure activation of signaling. Show less

This study examines to what extent plasma linoleic acid (LA) is modified by adiposity, and explores any association between plasma LA, demographics, dietary intakes, markers of metabolic health, and haplotypes of the fatty acid desaturase (FADS) 1/2 genes. A total of 820 participants with fasting blood samples from the Irish National Adult Nutrition Survey are studied. Plasma fatty acids are determined using GC-MS. Fifteen SNPs of FADS 1/2 genes are genotyped. Plasma LA decreases, while γ-linoleic acid and dihomo-γ-linoleic acid increases in overweight/obese participants (p ≤ 0.002). Participants in the highest quartile of plasma LA show decreased plasma markers of de novo lipogenesis, insulin resistance, and of inflammation (TNF-α, PAI-1) (p ≤ 0.005). Adiposity (waist circumference and body fat) is strongly inversely associated with plasma LA accounting for 11.8% of variance observed, which is followed by FADS1/2 haplotypes (3.9%), quantity and quality of carbohydrate intakes (3.8%), dietary PUFA intakes (3.7%), systolic blood pressure (3.6%), and age (3.2%). Plasma LA is inversely associated with adiposity, followed by haplotypes of FADS1/2 genes, carbohydrate intakes, and dietary PUFA intakes. The association observed between plasma LA and adiposity may be linked to decreased de novo lipogenesis, insulin resistance, and inflammation. Show less