Deletion of p75NTR rescues the synaptic but not the inflammatory status in the brain of a mouse model for Alzheimer’s disease

Introduction Alzheimer's disease (AD), is characterized by a gradual cognitive decline associated with the accumulation of Amyloid beta (Aβ)-oligomers, progressive neuronal degeneration and chronic neuroinflammation. Among the receptors shown to bind and possibly transduce the toxic effects of Aβ-oligomers is the p75 neurotrophin receptor (p75NTR). Interestingly, p75NTR mediates several crucial processes in the nervous system, including neuronal survival and apoptosis, maintenance of the neuronal architecture, and plasticity. Furthermore, p75NTR is also expressed in microglia, the resident immune cells of the brain, where it is markedly increased under pathological conditions. These observations indicate p75NTR as a potential candidate for mediating Aβ-induced toxic effects at the interface between the nervous and the immune system, thereby potentially participating in the crosstalk between these two systems. Methods Here we used APP/PS1 transgenic mice (APP/PS1tg) and compared the Aβ-induced alterations in neuronal function, chronic inflammation as well as their cognitive consequences between 10 months old APP/PS1tg and APP/PS1tg x p75NTRexonIV knockout mice. Results Electrophysiological recordings show that a loss of p75NTR rescues the impairment in long-term potentiation at the Schaffer collaterals in the hippocampus of APP/PS1tg mice. Interestingly, however loss of p75NTR does not influence the severity of neuroinflammation, microglia activation or the decline in spatial learning and memory processes observed in APP/PS1tg mice. Conclusion Together these results indicate that while a deletion of p75NTR rescues the synaptic defect and the impairment in synaptic plasticity, it does not affect the progression of the neuroinflammation and the cognitive decline in a mouse model for AD

Acute alcohol consumption increases systemic endotoxin bioactivity for days in healthy volunteers - with reduced intestinal barrier loss in female

Objective: Trauma is the most common cause of death among young adults. Alcohol intoxication plays a significant role as a cause of accidents and as a potent immunomodulator of the post-traumatic response to tissue injury. Polytraumatized patients are frequently at risk to developing infectious complications, which may be aggravated by alcohol-induced immunosuppression. Systemic levels of integral proteins of the gastrointestinal tract such as syndecan-1 or intestinal fatty acid binding proteins (FABP-I) reflect the intestinal barrier function. The exact impact of acute alcohol intoxication on the barrier function and endotoxin bioactivity have not been clarified yet. Methods: 22 healthy volunteers received a precisely defined amount of alcohol (whiskey–cola) every 20 min over a period of 4 h to reach the calculated blood alcohol concentration (BAC) of 1‰. Blood samples were taken before alcohol drinking as a control, and after 2, 4, 6, 24 and 48 h after beginning with alcohol consumption. In addition, urine samples were collected. Intestinal permeability was determined by serum and urine values of FABP-I, syndecan-1, and soluble (s)CD14 as a marker for the endotoxin translocation via the intestinal barrier by ELISA. BAC was determined. Results: Systemic FABP-I was significantly reduced 2 h after the onset of alcohol drinking, and remained decreased after 4 h. However, at 6 h, FABP-I significantly elevated compared to previous measurements as well as to controls (p < 0.05). Systemic sCD14 was significantly elevated after 6, 24 and 48 h after the onset of alcohol consumption (p < 0.05). Systemic FABP-I at 2 h after drinking significantly correlated with the sCD14 concentration after 24 h indicating an enhanced systemic LPS bioactivity. Women showed significantly lower levels of syndecan-1 in serum and urine and urine for all time points until 6 h and lower FABP-I in the serum after 2 h. Conclusions: Even relative low amounts of alcohol affect the immune system of healthy volunteers, although these changes appear minor in women. A potential damage to the intestinal barrier and presumed enhanced systemic endotoxin bioactivity after acute alcohol consumption is proposed, which represents a continuous immunological challenge for the organism and should be considered for the following days after drinking

Interleukin (IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17

Peroral infection with Toxoplasma gondii leads to the development of small intestinal inflammation dependent on Th1 cytokines. The role of Th17 cells in ileitis is unknown. We report interleukin (IL)-23–mediated gelatinase A (matrixmetalloproteinase [MMP]-2) up-regulation in the ileum of infected mice. MMP-2 deficiency as well as therapeutic or prophylactic selective gelatinase blockage protected mice from the development of T. gondii–induced immunopathology. Moreover, IL-23–dependent up-regulation of IL-22 was essential for the development of ileitis, whereas IL-17 was down-regulated and dispensable. CD4+ T cells were the main source of IL-22 in the small intestinal lamina propria. Thus, IL-23 regulates small intestinal inflammation via IL-22 but independent of IL-17. Gelatinases may be useful targets for treatment of intestinal inflammation