Homo and heterozygote cx3cr1 mutant mice, which harbor a green fluorescent protein (EGFP) in their cx3cr1 loci, represent a widely used animal model to study microglia and peripheral myeloid cells. Here we report that microglia in the dentate gyrus (DG) of cx3cr1 −/− mice displayed elevated microglial sirtuin 1 (SIRT1) expression levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) p65 activation, despite unaltered morphology when compared to cx3cr1 +/− or cx3cr1 +/+ controls. This phenotype was restricted to the DG and accompanied by reduced adult neurogenesis in cx3cr1 −/− mice. Remarkably, adult neurogenesis was not affected by the lack of the CX3CR1-ligand, fractalkine (CX3CL1). Mechanistically, pharmacological activation of SIRT1 improved adult neurogenesis in the DG together with an enhanced performance of cx3cr1 −/− mice in a hippocampus-dependent learning and memory task. The reverse condition was induced when SIRT1 was inhibited in cx3cr1 −/− mice, causing reduced adult neurogenesis and lowered hippocampal cognitive abilities. In conclusion, our data indicate that deletion of CX3CR1 from microglia under resting conditions modifies brain areas with elevated cellular turnover independent of CX3CL1.

The role of microglia in amyloid-β (Aβ) deposition is controversial. In the present study, an organotypic hippocampal slice culture (OHSC) system with an in vivo-like microglial-neuronal environment was used to investigate the potential contribution of microglia to Aβ plaque formation. We found that microglia ingested Aβ, thereby preventing plaque formation in OHSCs. Conversely, Aβ deposits formed rapidly in microglia-free wild-type slices. The capacity to prevent Aβ plaque formation was absent in forebrain microglia from young adult but not juvenile 5xFamilial Alzheimer’s disease (FAD) mice. Since no loss of Aβ clearance capacity was observed in both wild-type and cerebellar microglia from 5xFAD animals, the high Aβ₁₋₄₂ burden in the forebrain of 5xFAD animals likely underlies the exhaustion of microglial Aβ clearance capacity. These data may therefore explain why Aβ plaque formation has never been described in wild-type mice and point to a beneficial role of microglia in AD pathology. We also describe a new method to study Aβ plaque formation in a cell culture setting.

Measurement of gylcated hemoglobin A1c (HbA1c) plays a central role in monitoring quality of antidiabetic therapy and in the diagnosis of diabetes. Several studies report increased levels of HbA1c in nondiabetic elderly. However, this observation did not reach incorporation into daily clinical practice or the respective guidelines. The present study aimed to evaluate HbA1c levels in relation to age in two independent population-based cohorts and to derive age-specific reference intervals. Four thousand two hundred sixty three participants from the Study of Health in Pomerania (SHIP-0) and 4402 participants from the independent study SHIP-Trend were included. HbA1c was determined by means of high-performance liquid chromatography. Multivariable linear regression models were performed. Reference intervals for HbA1c were determined. Reference intervals were derived from a healthy subpopulation with the upper reference limit (URL) for HbA1c of 42.1 mmol/Mol (6.0%) for individuals aged 20–39 years increasing to 43.2 mmol/Mol (6.1%) for individuals aged 40–59 years. For people aged ≥60 years the URL was 47.5 mmol/Mol (6.5%). In both study populations an increase in HbA1c with age was observed. ANOVA revealed up to 8.5 mmol/Mol (0.77%) or 7.3 mmol/Mol (0.68%) higher estimated mean levels of HbA1c in the oldest compared to the youngest age group in SHIP-0 or SHIP-trend, respectively. Linear regression analyses confirmed the positive associations of HbA1c with age which was independent of BMI The present study confirmed the previously observed increase of HbA1c with increasing age in non-diabetic individuals. As a consequence age-dependent reference values for HbA1c were derived from two large and well defined reference populations. Implementation of them into daily practice may improve patient care and diagnosis of diabetes and reduce the risk of misdiagnosis and subsequent overtreatment of diabetes in elderly patients.