👤 Anders Olofsson

The efficient clearance of IAPP oligomers (IAPPo) by autoantibodies is crucial as increased plasma levels of IAPPo can induce microvascular alterations and Alzheimer's disease (AD)-characteristic amyloid-β deposition in the brain. We have recently demonstrated that plasma immunoglobulin (Ig) A levels against IAPPo, but not IgG, are reduced in an Apolipoprotein E (APOE) ε4 allele dose-dependent manner. In this study, we aimed to investigate if this APOE genotype-dependent impact can be explained by differences in IAPP epitope recognition by IgA and IgG. We found that the specificity for IAPP epitopes does not differ between IgG and IgA autoantibodies and that IgG and IgA autoantibodies are directed foremost against the C-terminus of the IAPP. However, IgG autoantibody levels against the N-terminus and midportion of IAPP increased significantly in AD patients with APOE44 compared to controls with APOE33, while the opposite was seen in IgA autoantibody levels. We propose that the IgG and IgA levels against different IAPP epitopes are APOE isotype-dependent, possibly due to differences in cytokine profile between various APOE genotypes or the need for different effector functions of IgG or IgA. Show less

Apolipoprotein-B (APOB)-containing lipoproteins cause atherosclerosis. Whether the vasculature is the initially responding site or if atherogenic dyslipidemia affects other organs simultaneously is unknown. Here we show that the liver responds to a dyslipidemic insult based on inducible models of familial hypercholesterolemia and APOB tracing. An acute transition to atherogenic APOB lipoprotein levels resulted in uptake by Kupffer cells and rapid accumulation of triglycerides and cholesterol in the liver. Bulk and single-cell RNA sequencing revealed a Kupffer-cell-specific transcriptional program that was not activated by a high-fat diet alone or detected in standard liver function or pathological assays, even in the presence of fulminant atherosclerosis. Depletion of Kupffer cells altered the dynamic of plasma and liver lipid concentrations, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins while simultaneously secreting atherosclerosis-modulating factors into plasma. Our results place Kupffer cells as key sentinels in organizing systemic responses to lipoproteins at the initiation of atherosclerosis. Show less

Apolipoprotein CIII (apoCIII) is associated with triglyceride (TG)-rich particles like VLDL and exerts an inhibitory effect of lipoprotein lipase. Increased levels are related to cardiovascular diseases and diabetes and therefore apoCIII has been proposed as a useful biomarker. Even if several commercial assays for measuring apoCIII in human plasma/serum are available, data is scarce concerning their reliability and none is used clinically. In the present study a comparative investigation has been done. Two ELISA-based methods (Cusabio Biotech and Assay Pro) and one nephelometric assay (Siemens Healthcare) were investigated. Serum and plasma samples were obtained from healthy volunteers and from samples sent to the Laboratory of Clinical Chemistry, preferably with higher levels of TGs. The Cusabio Biotech assay did not yield any valid results. However, both the methods from Assay Pro and Siemens Healthcare showed good performance with similar dynamic ranges. The latter assay had lower CV and required less work. In healthy individuals, apoCIII levels were not affected by fasting, freezing or thawing, nor did we find any gender differences. Individuals with elevated levels of TG displayed higher apoCIII values. Females with oral intake of contraceptives had higher levels. In conclusion, the nephelometric assay showed the best performance with the lowest CV, was less labor intensive than an assay based on ELISA and could therefore be suitable for clinical use. Show less

To evaluate circulating adrenal steroid hormones, cortisol diurnal rhythm and the negative feedback function of the cortisol axis in patients with dystrophia myotonica (DyM), a disease where metabolic disturbances, peripheral insulin insensitivity and cognitive dysfunction are common features. Morning serum levels of dehydroepiandrosterone sulphate, androstenedione, 17 alpha-hydroxy progesterone and cortisol; morning serum levels of testosterone and insulin; diurnal rhythm of saliva cortisol; and an overnight dexamethasone suppression test, together with a cognitive screening test in men with DyM and in controls. Outpatient clinic in co-operation with Umeå University Hospital. Fifteen men with DyM and 13 age-matched controls. Adrenal steroid hormone levels, diurnal rhythm of saliva cortisol, dexamethasone suppression test and Mini Mental State Examination scores. Morning serum levels of dehydroepiandrosterone sulphate, androstenedione and 17 alpha-hydroxy progesterone were significantly decreased in DyM after inclusion of age and body mass index in multiple regression analyses (48, 26 and 32% decreases, respectively). An abnormal diurnal rhythm of saliva cortisol was present in all patients, mean saliva cortisol levels being significantly increased (33%) in DyM patients. Dexamethasone suppressibility did not differ between groups. DyM patients scored significantly lower on the Mini Mental State Examination (P < 0.001). These results indicate an abnormal adrenal steroid hormone secretion in DyM, which may contribute to peripheral insulin sensitivity as well as cognitive impairment in these patients. Show less