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Background: Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. The relation between APOE4 genotype and cPLA2 activity is not known.Methods: Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress. Results: Greater cPLA2 phosphorylation and activity was identified in ApoE4 compared to ApoE3 in primary astrocytes and brains of ApoE-targeted replacement (ApoE-TR) mice. These differences were also demonstrated in brain homogenates from the inferior frontal cortex from AD patients carrying APOE3/4 compared to APOE3/3. Higher cPLA2 activation with APOE4 was associated with greater activation of the MAPK p38 pathway in human postmortem frontal cortical synaptosomes and astrocytes, as well as with higher levels of leukotriene B4 (LTB4), reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) in astrocytes. Inhibition of cPLA2 reduced LTB4, ROS, and iNOS levels in ApoE4 primary astrocytes to those in ApoE3 astrocytes. Conclusions: Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.

To assess associations that endogenous estradiol and testosterone levels have with cognitive function in older adults with Type 2 diabetes mellitus (T2DM).We use data from the Look AHEAD clinical trial of behavioral weight loss. Endogenous estradiol and total testosterone levels were determined using stored serum from 996 individuals, mean age 69 years, at two times (averaging 4 years apart) during years 8-18 of follow-up. One to four standardized assessments of attention, executive function, memory, and verbal fluency were collected during this follow-up. Mixed effects models and multiple imputation were used to assess associations that estradiol and total testosterone levels had with body mass index and cognitive function.Estradiol levels were not associated with cognitive function in either sex. Total testosterone levels were not associated with cognitive function in women, but greater total testosterone levels were associated with better verbal fluency in men (p 0.001), most strongly among those carrying the APOE-e4 allele (interaction p = 0.02). The weight loss intervention left a legacy of relatively lower cognitive functioning among women, which was not mediated by current levels of sex hormones.Behavioral weight loss intervention does not affect cognitive functioning through mechanisms related to estradiol or testosterone.gov Identifier: NCT00017953.

Introduction It is unknown whether rates of cognitive decline differ between older women and men with type 2 diabetes (T2D) and overweight or obesity. Methods Two to four cognitive assessments were obtained across up to 10 years from 2799 adults (mean age 68 years; 62% women) with T2D who had been enrolled in a clinical trial of weight loss intervention. Sex‐related differences in means and rates of decline of cognitive scores were assessed. Results Women outperformed men in verbal learning and processing speed (P

Background Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and risk of developing late-onset Alzheimer disease (AD), but the mechanisms for this association are not clear. Activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within plaques of the AD brain. The relation between APOE4 genotype and cPLA2 activity is not known. Methods Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation and activity in relation to measures of inflammation and oxidative stress. Results Greater cPLA2 phosphorylation and activity were identified in ApoE4 compared to ApoE3 in primary astrocytes and brains of ApoE-targeted replacement (ApoE-TR) mice. These differences were also demonstrated in brain homogenates from the inferior frontal cortex from AD patients carrying APOE3/4 compared to APOE3/3. Higher cPLA2 activation with APOE4 was associated with greater activation of the MAPK p38 pathway, as well as with higher levels of leukotriene B4 (LTB4), reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS). Inhibition of cPLA2 reduced LTB4, ROS and iNOS levels in ApoE4 primary astrocytes to those of ApoE3 astrocytes. Conclusions Our findings implicate greater activation of cPLA2 signaling system with APOE4, that could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.

The apoC-III proteoform containing two sialic acid residues (apoC-III2) has different in vitro effects on lipid metabolism compared with asialylated (apoC-III0) or the most abundant monosialylated (apoC-III1) proteoforms. Cross-sectional and longitudinal associations between plasma apoC-III proteoforms (by mass spectrometric immunoassay) and plasma lipids were tested in two randomized clinical trials: ACT NOW, a study of pioglitazone in subjects with impaired glucose tolerance (n = 531), and RACED (n = 296), a study of intensive glycemic control and atherosclerosis in type 2 diabetes patients. At baseline, higher relative apoC-III2 and apoC-III2/apoC-III1 ratios were associated with lower triglycerides and total cholesterol in both cohorts, and with lower small dense LDL in the RACED. Longitudinally, changes in apoC-III2/apoC-III1 were inversely associated with changes in triglycerides in both cohorts, and with total and small dense LDL in the RACED. apoC-III2/apoC-III1 was also higher in patients treated with PPAR-γ agonists and was associated with reduced cardiovascular events in the RACED control group. Ex vivo studies of apoC-III complexes with higher apoC-III2/apoC-III1 showed attenuated inhibition of VLDL uptake by HepG2 cells and LPL-mediated lipolysis, providing possible functional explanations for the inverse association between a higher apoC-III2/apoC-III1 and hypertriglyceridemia, proatherogenic plasma lipid profiles, and cardiovascular risk.

Serum Amyloid A (SAA) is an acute phase reactant protein that exists in multiple isoforms, can form HDL, and participates in cholesterol efflux. In vitro studies suggest that the SAA 2.1 isoform has an increased capacity to mediate cholesterol efflux compared to the other isoforms. We examined SAA isoforms using a novel mass spectrometric immunoassay (MSIA) and HDL’s cholesterol efflux capacity (via ABCA-1 and SR-BI) in samples from 59 subjects with (n=33) and without type 2 diabetes (n=26). SAA 1.1 levels were detectable in 58, SAA 2.1 in 14 and SAA 2.2 in 36 of the 59 subjects. SAA 2.1 levels significantly correlated with SR-BI cholesterol efflux (r=0.71, p=0.01, n=14), but not ABCA-1 mediated efflux (r=0.1, P=0.1). This correlation was not explained by changes in HDL phospholipids, Apo A-I or HDL cholesterol levels. In contrast, SAA 2.2 or 1.1 levels did not correlate with changes in SR-BI or ABCA-1 mediated efflux. Although the SAA 2.1 isoform is less frequently detected in plasma, our data confirm that it is closely linked with HDL mediated cholesterol efflux, particularly that is SR-BI mediated.

Taylor A, Westveld AH, Szkudlinska M, et al. J Pain Res. 2013;6:755–763. The notes section for Table 2 should read:Notes: Sections 1 and 2 are adapted from the short-form McGill pain questionnaire.19 Patients were asked to identify their pain with the provided scale. Melzack R. The short-form McGill Pain Questionnaire. Pain. 1987;30(2):191–197. The figure has been reproduced with permission of the International Association for the Study of Pain® (IASP). The figure may not be reproduced for any other purpose without permission.Read the original article