No abstract

Membrane transporters such as ATP-binding cassette (ABC) and solute carrier (SLC) transporters expressed at the neurovascular unit (NVU) play an important role in drug delivery to the brain and have been demonstrated to be involved in Alzheimer’s disease (AD) pathogenesis. However, our knowledge of quantitative changes in transporter absolute protein expression and functionality in vivo in NVU in AD patients and animal models is limited. The study aim was to investigate alterations in protein expression of ABC and SLC transporters in the isolated brain microvessels and brain prefrontal cortices of a widely used model of familial AD, 5xFAD mice (8 months old), using a sensitive liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomic approach. Moreover, we examined alterations in brain prefrontal cortical and plasmatic levels of transporter substrates in 5xFAD mice compared to age-matched wild-type (WT) controls. ASCT1 (encoded by Slc1a4) protein expression in the isolated brain microvessels and brain prefrontal cortices of 5xFAD mice was twice higher compared to WT controls (p = 0.01). Brain cortical levels of ASCT1 substrate, serine, were increased in 5xFAD mice compared to WT animals. LAT1 (encoded by Slc7a5) and 4F2hc (encoded by Slc3a2) protein expressions were significantly altered in the isolated brain microvessels of 5xFAD mice compared to WT controls (p = 0.008 and p = 0.05, respectively). Overall, the study provides important information, which is crucial for the optimal use of the 5xFAD mouse model in AD drug development and for investigating novel drug delivery approaches. In addition, the findings of the study shed light on the novel potential mechanisms underlying AD pathogenesis.

It has been postulated that the activation of NMDA receptors (NMDAr) and nitric oxide (NO) production in the hippocampus is involved in the behavioral consequences of stress. Stress triggers NMDAr‐induced calcium influx in limbic areas, such as the hippocampus, which in turn activates neuronal NO synthase (nNOS). Inhibition of nNOS or NMDAr activity can prevent stress‐induced effects in animal models, but the molecular mechanisms behind this effect are still unclear. In this study, cultured hippocampal neurons treated with NMDA or dexamethasone showed an increased of DNA methyltransferase 3b (DNMT3b) mRNA expression, which was blocked by pre‐treatment with nNOS inhibitor nω‐propyl‐l‐arginine (NPA). In rats submitted to the Learned Helplessness paradigm (LH), we observed that inescapable stress increased DNMT3b mRNA expression at 1h and 24h in the hippocampus. The NOS inhibitors 7‐NI and aminoguanidine (AMG) decreased the number of escape failures in LH and counteracted the changes in hippocampal DNMT3b mRNA induced in this behavioral paradigm. Altogether, our data suggest that NO produced in response to NMDAr activation following stress upregulates DNMT3b in the hippocampus.

Global emphasis on enhancing prevention and treatment strategies necessitates increased understanding of biological mechanisms of psychopathology. Plasma proteomics is a powerful tool that has been applied in the context of specific mental disorders for biomarker identification. The p-factor, also known as the "general psychopathology factor", is a concept in psychopathology suggesting that there is a common underlying factor that contributes to the development of various forms of mental disorders. It has been proposed that the p-factor can be used to understand the overall mental health status of an individual. Here we aimed to discover plasma proteins associated with the p-factor in 775 young adults in the FinnTwin12 cohort. Using liquid chromatography-tandem mass spectrometry, 14 proteins with a significant connection with the p-factor were identified, 9 of which were linked to epidermal growth factor receptor (EGFR) signalling. This exploratory study provides new insight into biological alterations associated with mental health status in young adults.

Fibromyalgia-like models in mice induced by reserpine have opened a new avenue to understanding the molecular mechanisms behind this complex and incapacitating pain syndrome. The kinin B1 receptor (B1R) contributes to mechanical allodynia and acute coping behavior in mice with inflammatory and immunological disorders. This study has replicated previous data where amine depletion induced by reserpine significantly decreased the dopamine and serotonin levels in the prefrontal cortex (PFC), hippocampus (HPC), and spinal cord of mice. The animals subjected to the reserpine fibromyalgia model also showed decreased paw withdrawal threshold (PWT) and increased the immobility time in the forced swimming test (FST). Genetic ablation of B1R or pharmacological blockade by selective kinin B1R antagonist R-715 (acute i.p. treatment) counteracted the mechanical allodynia and increased immobility time induced by reserpine. However, neither pharmacological nor genetic inhibition of B1R reversed monoamine depletion. Our data confirm that reserpine induced a fibromyalgia-like phenotype in mice and reiterated the role of B1R on acute coping behavior and nociception modulation.