Little is known about the mechanisms converting psychosocial stress into cellular dysfunction. Various genes, up-regulated in atherosclerosis but also by psychosocial stress, are controlled by the transcription factor nuclear factor κB (NF-κB). Therefore, NF-κB is a good candidate to convert psychosocial stress into cellular activation. Volunteers were subjected to a brief laboratory stress test and NF-κB activity was determined in peripheral blood mononuclear cells (PBMC), as a window into the body and because PBMC play a role in diseases such as atherosclerosis. In 17 of 19 volunteers, NF-κB was rapidly induced during stress exposure, in parallel with elevated levels of catecholamines and cortisol, and returned to basal levels within 60 min. To model this response, mice transgenic for a strictly NF-κB-controlled β-globin transgene were stressed by immobilization. Immobilization resulted in increased β-globin expression, which could be reduced in the presence of the α1-adrenergic inhibitor prazosin. To define the role of adrenergic stimulation in the up-regulation of NF-κB, THP-1 cells were induced with physiological amounts of catecholamines for 10 min. Only noradrenaline resulted in a dose- and time-dependent induction of NF-κB and NF-κB-dependent gene expression, which depended on pertussis-toxin-sensitive G protein-mediated phosphophatidylinositol 3-kinase, Ras/Raf, and mitogen-activated protein kinase activation. Induction was reduced by α ₁ - and β-adrenergic inhibitors. Thus, noradrenaline-dependent adrenergic stimulation results in activation of NF-κB in vitro and in vivo . Activation of NF-κB represents a downstream effector for the neuroendocrine response to stressful psychosocial events and links changes in the activity of the neuroendocrine axis to the cellular response.

According to the neurovascular hypothesis, impairment of low-density lipoprotein receptor–related protein-1 (LRP1) in brain capillaries of the blood-brain barrier (BBB) contributes to neurotoxic amyloid-β (Aβ) brain accumulation and drives Alzheimer’s disease (AD) pathology. However, due to conflicting reports on the involvement of LRP1 in Aβ transport and the expression of LRP1 in brain endothelium, the role of LRP1 at the BBB is uncertain. As global Lrp1 deletion in mice is lethal, appropriate models to study the function of LRP1 are lacking. Moreover, the relevance of systemic Aβ clearance to AD pathology remains unclear, as no BBB-specific knockout models have been available. Here, we developed transgenic mouse strains that allow for tamoxifen-inducible deletion of Lrp1 specifically within brain endothelial cells (Slco1c1-CreER^T2 Lrp1^fl/fl mice) and used these mice to accurately evaluate LRP1-mediated Aβ BBB clearance in vivo. Selective deletion of Lrp1 in the brain endothelium of C57BL/6 mice strongly reduced brain efflux of injected [¹²⁵I] Aβ_1–42. Additionally, in the 5xFAD mouse model of AD, brain endothelial–specific Lrp1 deletion reduced plasma Aβ levels and elevated soluble brain Aβ, leading to aggravated spatial learning and memory deficits, thus emphasizing the importance of systemic Aβ elimination via the BBB. Together, our results suggest that receptor-mediated Aβ BBB clearance may be a potential target for treatment and prevention of Aβ brain accumulation in AD.

In ischemic stroke, the necrotic core is surrounded by a zone of inflammation, in which delayed cell death aggravates the initial insult. Here, we provide evidence that the receptor for advanced glycation end products (RAGE) functions as a sensor of necrotic cell death and contributes to inflammation and ischemic brain damage. The RAGE ligand high mobility group box 1 (HMGB1) was elevated in serum of stroke patients and was released from ischemic brain tissue in a mouse model of cerebral ischemia. A neutralizing anti-HMGB1 antibody and HMGB1 box A, an antagonist of HMGB1 at the receptor RAGE, ameliorated ischemic brain damage. Interestingly, genetic RAGE deficiency and the decoy receptor soluble RAGE reduced the infarct size.In vitro, expression of RAGE in (micro)glial cells mediated the toxic effect of HMGB1. Addition of macrophages to neural cultures further enhanced the toxic effect of HMGB1. To test whether immigrant macrophages in the ischemic brain mediate the RAGE effect, we generated chimeric mice by transplanting RAGE^−/−bone marrow to wild-type mice. RAGE deficiency in bone marrow-derived cells significantly reduced the infarct size. Thus, HMGB1–RAGE signaling links necrosis with macrophage activation and may provide a target for anti-inflammatory therapy in stroke.

Background and Purpose— The potential neuroprotective effect of the granulocyte colony–stimulating factor (G-CSF) after glutamate-induced excitotoxicity in cell culture and after focal cerebral ischemia in rats was studied. We hypothesized the existence of the G-CSF receptor (G-CSFR) as a main G-CSF effector on neurons, and immunohistochemistry, immunoblotting, and polymerase chain reaction were performed. The G-CSFR–mediated action was studied by activation of signal transducer(s) and activator(s) of transcription-3 (STAT3) in the periphery of the infarction. Methods— Neuroprotection of various G-CSF concentrations on glutamate-induced excitotoxicity was studied in cell culture. In vivo, ischemia was induced by use of a suture occlusion model of the middle cerebral artery (90-minute occlusion) in the rat. Thirty minutes after the induction of ischemia, the animals (n=12 per group) received G-CSF at 60 μg/kg body wt IV for 90 minutes or vehicle (saline). Infarct volume was calculated on the basis of 2,3,5-triphenyltetrazolium chloride staining 24 hours after ischemia. Expression of the G-CSFR was studied by immunohistochemistry and verified by reverse transcription–polymerase chain reaction and immunoblotting. Expression of STAT3 was determined by immunohistochemistry. Results— In cell culture, G-CSF exhibited a significant neuroprotective effect after glutamate-induced excitotoxicity ( P <0.05). A G-CSF concentration of 10 ng/mL was maximally effective, resulting in a nearly complete protection. In vivo, G-CSF reduced infarct volume to 47% (132.0±112.7 mm ³ versus 278.9±91.6 mm ³ [ P <0.05] in the control group). Immunohistochemistry, Western blotting, and reverse transcription–polymerase chain reaction revealed the existence of G-CSFRs in neurons and glial cells. Animals treated with G-CSF significantly upregulated STAT3 in the periphery of the infarction compared with control animals ( P <0.05). Conclusions— G-CSF achieved a significant neuroprotective effect in cell culture and after intravenous administration after stroke. Increased STAT3 expression in the penumbra of G-CSF–treated rats suggests mediation by G-CSFR.