👤 Michael Kruse

Early and accurate detection of Alzheimer's disease (AD) is essential for timely intervention and development of disease-modifying treatments. The DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) provides a deeply phenotyped cohort covering preclinical and early clinical stages, including subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Astrocyte reactivity and its biomarkers, particularly glial fibrillary acidic protein (GFAP), have gained increasing attention in AD research; however, the relationship between GFAP and amyloid in early disease, as well as its potential prognostic value beyond its association with amyloid status, remains insufficiently understood. To evaluate the performance of CSF and plasma GFAP across early disease stages, compare these measures according to amyloid status, and assess the prognostic value of GFAP for clinical progression across diagnostic stages during longitudinal follow-up. This study used data from the multicenter DELCODE cohort in Germany, including participants with available plasma and/or CSF samples and standardized clinical, cognitive, imaging, and biomarker assessments. GFAP concentrations in plasma and CSF were quantified using validated immunoassay platforms. Standard CSF AD biomarkers and ApoE genotype were measured using established assays. Amyloid status was defined by the CSF Aβ42/40 ratio. Longitudinal follow-up occurred annually for up to ∼10 years, with clinical conversion determined according to NIA-AA criteria. Plasma and CSF GFAP increased across the AD continuum, with higher levels in MCI and AD (p < 0.001). Plasma GFAP showed a stronger association with amyloid status than CSF GFAP across all groups. In MCI, plasma GFAP combined with age and ApoE4 yielded an AUC of 0.87. Elevated plasma GFAP predicted increased risk of conversion to MCI (HR = 2.19, p < 0.001; adjusted HR = 1.70, p = 0.0056) and AD dementia (HR = 3.5; adjusted HR = 2.49 both p < 0.001). Plasma GFAP is a sensitive, minimally invasive biomarker with diagnostic relevance for amyloid detection and prognostic relevance for clinical progression in early AD. Show less

Adipose-derived mesenchymal stem cells (ADSCs) are promising candidates for novel cell therapeutic applications. Hibernating brown bears sustain tissue integrity and function via unknown mechanisms, which might be plasma borne. We hypothesized that plasma from hibernating bears may increase the expression of favorable factors from human ADSCs. In an experimental study, ADSCs from patients with ischemic heart disease were treated with interventional media containing plasma from hibernating and active bears, respectively, and with control medium. Extracted RNA from the ADSCs was sequenced using next generation sequencing. Statistical analyses of differentially expressed genes were performed using fold change analysis, pathway analysis, and gene ontology. As a result, we found that genes associated with inflammation, such as IGF1, PGF, IL11, and TGFA, were downregulated by > 10-fold in ADSCs treated with winter plasma compared with control. Genes important for cardiovascular development, ADM, ANGPTL4, and APOL3, were upregulated in ADSCs when treated with winter plasma compared with summer plasma. ADSCs treated with bear plasma, regardless if it was from hibernating or active bears, showed downregulation of IGF1, PGF, IL11, INHBA, IER3, and HMOX1 compared with control, suggesting reduced cell growth and differentiation. This can be summarized in the conclusion that plasma from hibernating bears suppresses inflammatory genes and activates genes associated with cardiovascular development in human ADSCs. Identifying the involved regulator(s) holds therapeutic potential. Show less

Hypertrophic cardiomyopathy (HCM) patients are at increased risk of ventricular arrhythmias and sudden cardiac death, which can occur even in the absence of structural changes of the heart. HCM mouse models suggest mutations in myofilament components to affect Ca Show less

Obesity has a multifactorial origin. It is known that alterations of the intra uterine milieu induce developmental programming effects leading to metabolic diseases in offspring. Obesity is diminished in mice lacking the glucose-dependent insulinotropic polypeptide receptor (Gipr Show less

Maternal obesity is a worldwide problem associated with increased risk of metabolic diseases in the offspring. Genetic deletion of the gastric inhibitory polypeptide (GIP) receptor (GIPR) prevents high-fat diet (HFD)-induced obesity in mice due to specific changes in energy and fat cell metabolism. We investigated whether GIP-associated pathways may be targeted by fetal programming and mimicked the situation by exposing pregnant mice to control or HFD during pregnancy (intrauterine [IU]) and lactation (L). Male wild-type (WT) and Gipr(-/-) offspring received control chow until 25 weeks of age followed by 20 weeks of HFD. Gipr(-/-) offspring of mice exposed to HFD during IU/L became insulin resistant and obese and exhibited increased adipose tissue inflammation and decreased peripheral tissue substrate utilization after being reintroduced to HFD, similar to WT mice on regular chow during IU/L. They showed decreased hypothalamic insulin sensitivity compared with Gipr(-/-) mice on control diet during IU/L. DNA methylation analysis revealed increased methylation of CpG dinucleotides and differential transcription factor binding of promoter regions of genes involved in lipid oxidation in the muscle of Gipr(-/-) offspring on HFD during IU/L, which were inversely correlated with gene expression levels. Our data identify GIP-regulated metabolic pathways that are targeted by fetal programming. Show less

Obesity is associated with elevated monocyte chemoattractant protein-1 (MCP-1), a proinflammatory chemokine related to diabetes and cardiovascular disease. Since obesity is triggered by energy dense diets, we hypothesised that nutrient induced intestinal hormones such as glucose-dependent insulinotropic peptide (GIP) may directly stimulate the release of chemokines from adipose tissue and induce low-grade inflammation. GIP effects on gene expression and secretion of inflammatory markers were studied by microarray analysis and PCR from human subcutaneous fat biopsies of slightly obese but healthy volunteers in the metabolic ward of German Institute of Human Nutrition, Department of Clinical Nutrition, Potsdam-Rehbrücke. To allocate the participants to the study arms they were numbered in order of their recruitment and then assigned to the groups by a random number generator. In a randomised, single-blind (participants) crossover design, the participants received GIP infusions in postprandial concentrations (2 pmol kg(-1) min(-1)) or saline (154 mmol/l NaCl) infusions for 240 min either alone, in combination with hyperinsulinaemic-euglycaemic (EU) or hyperinsulinaemic-hyperglycaemic (HC) clamps. Possible mechanisms of GIP effects were investigated in single and co-cultures of macrophage and adipocyte cell lines and in primary human monocytes, macrophages and adipocytes. A total of 17 participants were randomised to the following groups: EU with GIP infusion (n = 9); EU with NaCl infusion (n = 9); HC with GIP infusion (n = 8); HC with NaCl infusion (n = 8); sole GIP infusion (n = 11) and sole placebo infusion (n = 11). All 17 individuals were analysed. The study is completed. In human subcutaneous adipose tissue (hSCAT), infusions of GIP significantly increased inflammatory chemokine and cytokine gene networks in transcriptomic microarray analyses. Particularly MCP-1 (180 ± 26%), MCP-2 (246 ± 58%) and IL-6 (234 ± 40%) mRNA levels in adipose tissue as well as circulating plasma concentrations of MCP-1 (165 ± 12 vs 135 ± 13 pg/ml; GIP vs saline after 240 min; p < 0.05 for all variables) in humans increased independently of circulating insulin or glucose plasma concentrations. GIP stimulation increased Mcp-1 mRNA-expression in co-cultures of differentiated 3T3L1-adipocytes and RAW 264.7 macrophages but not in the isolated cell lines. Similarly, GIP increased MCP-1 transcripts in co-cultures of primary human macrophages with human adipocytes. GIP receptor (GIPR) transcripts were present in primary monocytes and the different cell lines and induced activation of extracellular related kinase (ERK) as well as increases in cAMP, indicating functional receptors. Our findings suggest that the nutrient induced gut hormone GIP may initiate adipose tissue inflammation by triggering a crosstalk of adipocytes and macrophages involving MCP-1. ClinicalTrials.gov NCT00774488. This work was supported by the German Research Foundation (DFG): grant No. Pf164/021002. Show less

Obesity, type 2 diabetes and associated metabolic diseases are characterized by low-grade systemic inflammation which involves interplay of nutrition and monocyte/macrophage functions. We suggested that some factors such as nutrient components, neuropeptides involved in the control of gastrointestinal functions, and gastrointestinal hormones might influence immune cell functions and in this way contribute to the disease pathogenesis. The aim of this study was to investigate the mRNA expression of twelve nutrition-associated receptors in peripheral blood mononuclear cells (PBMC), isolated monocytes and monocyte-derived macrophages and their regulation under the switching from the high-carbohydrate low-fat diet to the low-carbohydrate high-fat (LC/HFD) isocaloric diet in healthy humans. The mRNA expression of receptors for short chain fatty acids (GPR41, GPR43), bile acids (TGR5), incretins (GIPR, GLP1R), cholecystokinin (CCKAR), neuropeptides VIP and PACAP (VIPR1, VIPR2), and neurotensin (NTSR1) was detected in PBMC and monocytes, while GPR41, GPR43, GIPR, TGR5, and VIPR1 were found in macrophages. Correlations of the receptor expression in monocytes with a range of metabolic and inflammatory markers were found. In non-obese subjects, the dietary switch to LC/HFD induced the increase of GPR43 and VIPR1 expression in monocytes. No significant differences of receptor expression between normal weight and moderately obese subjects were found. Our study characterized for the first time the expression pattern of nutrition-associated receptors in human blood monocytes and its dietary-induced changes linking metabolic responses to nutrition with immune functions in health and metabolic diseases. Show less

Autophagy is a catabolic process that maintains cellular homeostasis by degradation of protein aggregates and selective removal of damaged organelles, e.g. mitochondria (mitophagy). Insulin resistance in skeletal muscle has been linked to mitochondrial dysfunction and altered protein metabolism. Here, we investigated whether abnormalities in autophagy are present in human muscle in obesity and type 2 diabetes. Using a case-control design, skeletal muscle biopsies obtained in the basal and insulin-stimulated states from patients with type 2 diabetes during both euglycaemia and hyperglycaemia, and from glucose-tolerant lean and obese individuals during euglycaemia, were used for analysis of mRNA levels, protein abundance and phosphorylation of autophagy-related proteins. Muscle transcript levels of autophagy-related genes (ULK1, BECN1, PIK3C3, ATG5, ATG7, ATG12, GABARAPL1, MAP1LC3B, SQSTM1, TP53INP2 and FOXO3A [also known as FOXO3]), including some specific for mitophagy (BNIP3, BNIP3L and MUL1), and protein abundance of autophagy-related gene (ATG)7 and Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), as well as content and phosphorylation of forkhead box O3A (FOXO3A) were similar among the groups. Insulin reduced lipidation of microtubule-associated protein light chain 3 (LC3)B-I to LC3B-II, a marker of autophagosome formation, with no effect on p62/sequestosome 1 (SQSTM1) content in muscle of lean and obese individuals. In diabetic patients, insulin action on LC3B was absent and p62/SQSTM1 content increased when studied under euglycaemia, whereas the responses of LC3B and p62/SQSTM1 to insulin were normalised during hyperglycaemia. Our results demonstrate that the levels of autophagy-related genes and proteins in muscle are normal in obesity and type 2 diabetes. This suggests that muscle autophagy in type 2 diabetes has adapted to hyperglycaemia, which may contribute to preserve muscle mass. Show less

Gestational diabetes (GD) alters normal fetal development and is related to a diabetogenic effect in the progeny. Liver X receptors (LXRs) are considered to be potential drug targets for the regulation, treatment, or prevention of diabetes. The aim of this study was to evaluate early and late changes of LXR in the hippocampus and hypothalamus of the male and female offspring of control (CO) and diabetic (DO) mothers. We used an experimental model of streptozotocin-induced GD to assess the protein expression of LXRα (NR1H3) and LXRβ (NR1H2) by western blotting. The tissues were obtained from CO and DO animals at postnatal day 1 (1D), day 10 (10D), and day 35 (35D) and 9 months (9M). In CO, the LXR expression showed significant differences among the groups, which were tissue- and receptor-specific (P<0.05). Sex differences in CO were found only in the hypothalamus for LXRβ expression at 35D and 9M (P<0.05). When CO and DO were compared, differences between them were observed in the majority of the studied groups at 1D (male hippocampus, LXRα 31% and LXRβ 161%; female hippocampus, LXRβ 165%; male hypothalamus, LXRβ 182%; and female hypothalamus, LXRα 85%; P<0.05). However, these differences disappeared later with the exception of LXRβ expression in the male hypothalamus (P<0.05). The area under the curve during the glucose tolerance test correlated negatively with LXRβ in CO but not in DO animals. Moreover, in a male DO subpopulation this correlation was positive as it occurs in intolerant animals. These results indicate that GD affects hypothalamic LXR expression differently in male and female offspring. Show less

Liver X receptor (LXR) α and β are nuclear receptors that are crucial for the regulation of carbohydrate and lipid metabolism. Activation of LXRs in the brain facilitates cholesterol clearance and improves cognitive deficits, thus they are considered as promising drug targets to treat diseases such as atherosclerosis and Alzheimer's disease. Nevertheless, little is known about the function and localization of LXRs in the brain. Here, we studied the expression of LXR in the brains of rats that received free access to 10% (w/v) fructose group (FG) in their beverages or water control drinks (control group (CG)). After 6 weeks rats in the FG presented with hypertriglyceridemia, hyperinsulinemia, and became glucose intolerant, suggesting a progression toward type 2 diabetes. We found that hypothalamic LXR expression was altered in fructose-fed rats. Rats in the FG presented with a decrease in LXRβ levels while showing an increase in LXRα expression in the hypothalamus but not in the hippocampus, cerebellum, or neocortex. Moreover, both LXRα and β expression correlated negatively with insulin and triglyceride levels. Interestingly, LXRβ showed a negative correlation with the area under the curve during the glucose tolerance test in the CG and a positive correlation in the FG. Immunocytochemistry revealed that the paraventricular and ventromedial nuclei express mainly LXRα whereas the arcuate nucleus expresses LXRβ. Both LXR immunosignals were found in the median preoptic area. This is the first study showing a relationship between glucose and lipid homeostasis and the expression of LXRs in the hypothalamus, suggesting that LXRs may trigger neurochemical and neurophysiological responses for the control of food intake and energy expenditure through these receptors. Show less