The therapeutic potential of placental growth factor (PlGF) and its receptor Flt1 in angiogenesis is poorly understood. Here, we report that PlGF stimulated angiogenesis and collateral growth in ischemic heart and limb with at least a comparable efficiency to vascular endothelial growth factor (VEGF). An antibody against Flt1 suppressed neovascularization in tumors and ischemic retina, and angiogenesis and inflammatory joint destruction in autoimmune arthritis. Anti-Flt1 also reduced atherosclerotic plaque growth and vulnerability, but the atheroprotective effect was not attributable to reduced plaque neovascularization. Inhibition of VEGF receptor Flk1 did not affect arthritis or atherosclerosis, indicating that inhibition of Flk1-driven angiogenesis alone was not sufficient to halt disease progression. The anti-inflammatory effects of anti-Flt1 were attributable to reduced mobilization of bone marrow-derived myeloid progenitors into the peripheral blood; impaired infiltration of Flt1-expressing leukocytes in inflamed tissues; and defective activation of myeloid cells. Thus, PlGF and Flt1 constitute potential candidates for therapeutic modulation of angiogenesis and inflammation.
The molecular pathways involved in the differentiation of hematopoietic progenitors are unknown. Here we report that chemokine-mediated interactions of megakaryocyte progenitors with sinusoidal bone marrow endothelial cells (BMECs) promote thrombopoietin (TPO)-independent platelet production. Megakaryocyte-active cytokines, including interleukin-6 (IL-6) and IL-11, did not induce platelet production in thrombocytopenic, TPO-deficient (Thpo(-/-)) or TPO receptor-deficient (Mpl(-/-)) mice. In contrast, megakaryocyte-active chemokines, including stromal-derived factor-1 (SDF-1) and fibroblast growth factor-4 (FGF-4), restored thrombopoiesis in Thpo(-/-) and Mpl(-/-) mice. FGF-4 and SDF-1 enhanced vascular cell adhesion molecule-1 (VCAM-1)- and very late antigen-4 (VLA-4)-mediated localization of CXCR4(+) megakaryocyte progenitors to the vascular niche, promoting survival, maturation and platelet release. Disruption of the vascular niche or interference with megakaryocyte motility inhibited thrombopoiesis under physiological conditions and after myelosuppression. SDF-1 and FGF-4 diminished thrombocytopenia after myelosuppression. These data suggest that TPO supports progenitor cell expansion, whereas chemokine-mediated interaction of progenitors with the bone marrow vascular niche allows the progenitors to relocate to a microenvironment that is permissive and instructive for megakaryocyte maturation and thrombopoiesis. Progenitor-active chemokines offer a new strategy to restore hematopoiesis in a clinical setting.
The incidence of Alzheimer disease (AD) and vascular dementia is greatly increased following cerebral ischemia and stroke in which hypoxic conditions occur in affected brain areas. ␤-Amyloid peptide (A␤), which is derived from the ␤-amyloid precursor protein (APP) by sequential proteolytic cleavages from ␤-secretase (BACE1) and presenilin-1 (PS1)/␥-secretase, is widely believed to trigger a cascade of pathological events culminating in AD and vascular dementia. However, a direct molecular link between hypoxic insults and APP processing has yet to be established. Here, we demonstrate that acute hypoxia increases the expression and the enzymatic activity of BACE1 by up-regulating the level of BACE1 mRNA, resulting in increases in the APP C-terminal fragment-␤ (␤CTF) and A␤. Hypoxia has no effect on the level of PS1, APP, and tumor necrosis factor-␣-converting enzyme (TACE, an enzyme known to cleave APP at the ␣-secretase cleavage site). Sequence analysis, mutagenesis, and gel shift studies revealed binding of HIF-1 to the BACE1 promoter. Overexpression of HIF-1␣ increases BACE1 mRNA and protein level, whereas down-regulation of HIF-1␣ reduced the level of BACE1. Hypoxic treatment fails to further potentiate the stimulatory effect of HIF-1␣ overexpression on BACE1 expression, suggesting that hypoxic induction of BACE1 expression is primarily mediated by HIF-1␣. Finally, we observed significant reduction in BACE1 protein levels in the hippocampus and the cortex of HIF-1␣ conditional knock-out mice. Our results demonstrate an important role for hypoxia/HIF-1␣ in modulating the amyloidogenic processing of APP and provide a molecular mechanism for increased incidence of AD following cerebral ischemic and stroke injuries.An important pathologic feature of Alzheimer disease (AD) 4 is formation of extracellular senile plaques in the brain, whose major components are small peptides called ␤-amyloid (A␤) derived from ␤-amyloid precursor protein (APP). APP is sequentially cleaved first by the ␤-secretase (␤-site amyloid precursor protein cleaving enzyme, BACE) and then by the ␥-secretase complex (including presenilin, nicastrin, APH-1, and PEN-2) to generate the heterogeneous A␤ species, mostly A␤40 but also the more deleterious A␤42. Alternatively, APP can be cleaved by ␣-secretase within the A␤ domain to generate non-amyloidogenic soluble APP␣ (sAPP␣) (1-3). The exact ␣-secretase is not known, but a disintegrin and metalloprotease domain 10 (ADAM10) and TNF-␣-converting enzyme (TACE) are two likely candidates (4, 5). It is widely believed that A␤ overproduction directly or indirectly initiates a cascade of neurodegenerative steps resulting in formation of senile plaques, neurofibrillary tangles, and neuronal loss, which characterize AD (6). Hence analysis of cellular regulation affecting A␤ generation, including identification of factors regulating the level/ activity of APP cleavage enzymes, should provide invaluable information for AD therapeutic intervention.BACE is a membrane-bound aspartic protease whose activity is t...
Alzheimer's disease (AD) is characterized by the accumulation of cerebral plaques composed of 40- and 42-amino acid beta-amyloid (Abeta) peptides, and autosomal dominant forms of AD appear to cause disease by promoting brain Abeta accumulation. Recent studies indicate that postmenopausal estrogen replacement therapy may prevent or delay the onset of AD. Here we present evidence that physiological levels of 17beta-estradiol reduce the generation of Abeta by neuroblastoma cells and by primary cultures of rat, mouse and human embryonic cerebrocortical neurons. These results suggest a mechanism by which estrogen replacement therapy can delay or prevent AD.
Epidemiological, clinical and experimental evidence suggests a link between type 2 diabetes and Alzheimer's disease (AD). Insulin modulates metabolism of ␤-amyloid precursor protein (APP) in neurons, decreasing the intracellular accumulation of ␤-amyloid (A␤) peptides, which are pivotal in AD pathogenesis. The present study investigates whether the widely prescribed insulin-sensitizing drug, metformin (Glucophage R ), affects APP metabolism and A␤ generation in various cell models. We demonstrate that metformin, at doses that lead to activation of the AMP-activated protein kinase (AMPK), significantly increases the generation of both intracellular and extracellular A␤ species. Furthermore, the effect of metformin on A␤ generation is mediated by transcriptional up-regulation of ␤-secretase (BACE1), which results in an elevated protein level and increased enzymatic activity. Unlike insulin, metformin exerts no effect on A␤ degradation. In addition, we found that glucose deprivation and various tyrphostins, known inhibitors of insulin-like growth factors/insulin receptor tyrosine kinases, do not modulate the effect of metformin on A␤. Finally, inhibition of AMP-activated protein kinase (AMPK) by the pharmacological inhibitor Compound C largely suppresses metformin's effect on A␤ generation and BACE1 transcription, suggesting an AMPK-dependent mechanism. Although insulin and metformin display opposing effects on A␤ generation, in combined use, metformin enhances insulin's effect in reducing A␤ levels. Our findings suggest a potentially harmful consequence of this widely prescribed antidiabetic drug when used as a monotherapy in elderly diabetic patients. A lzheimer's disease (AD) is a devastating neurodegenerative disorder, with aging, genetic, and environmental factors contributing to its development and progression. AD is not only characterized by pathological deposition of A␤ peptides and neurofibrillary tangles but is also associated with microgliamediated inflammation and dysregulated lipid homeostasis and glucose metabolism. Amyloid peptides are derived from sequential proteolytic cleavages of full-length amyloid precursor protein (APP) by ␤-secretase (BACE1) and ␥-secretase. Full-length APP can undergo alternative processing by ␣-secretase, releasing a soluble fragment (sAPP␣) extracellularly, which precludes A␤ formation. Compelling evidence indicates that A␤, especially the oligomers, are toxic to neurons; excessive generation and accumulation of A␤ peptides in neurons is believed to initiate the pathological cascade in AD (1-3).Epidemiological studies strongly suggest that metabolic defects correlate with the functional alterations associated with aging of the brain and with AD pathogenesis (4-11). The vast majority of AD cases are late onset and sporadic in origin with aging being the most profound risk factor. Insulin signaling is known to be involved in the process of brain aging (12)(13)(14)(15)(16)(17)(18)(19)(20). Insulin dysfunction/resistance in diabetes mellitus (DM) is not only a common syndrome ...
BackgroundNeuroinflammation is implicated in the development and progression of many neurodegenerative diseases. Conditions that lead to a peripheral immune response are often associated with inflammation in the central nervous system (CNS), suggesting a communication between the peripheral immune system and the neuroimmune system. The underlying mechanism of this relationship remains largely unknown; however, experimental studies have demonstrated that exposure to infectious stimuli, such as lipopolysaccharide (LPS) or high-fat diet (HFD) feeding, result in profound peripheral- and neuro-inflammation.MethodsUsing the model of endotoxemia with LPS, we studied the role of serum-derived exosomes in mediating neuroinflammation. We purified circulating exosomes from the sera of LPS-challenged mice, which were then intravenously injected into normal adult mice.ResultsWe found that the recipient mice that received serum-derived exosomes from LPS-challenged mice exhibited elevated microglial activation. Moreover, we observed astrogliosis, increased systemic pro-inflammatory cytokine production, and elevated CNS expression of pro-inflammatory cytokine mRNA and the inflammation-associated microRNA (miR-155) in these recipient mice. Gene expression analysis confirmed that many inflammatory microRNAs were significantly upregulated in the purified exosomes under LPS-challenged conditions. We observed accumulated signaling within the microglia of mice that received tail-vein injections of fluorescently labeled exosomes though the percentage of those microglial cells was found low. Finally, purified LPS-stimulated exosomes from blood when infused directly into the cerebral ventricles provoked significant microgliosis and, to a lesser extent, astrogliosis.ConclusionsThe experimental results suggest that circulating exosomes may act as a neuroinflammatory mediator in systemic inflammation.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-1038-8) contains supplementary material, which is available to authorized users.
Vascular endothelial cadherin (VE-cadherin)is an endothelial-specific, trans-membrane protein that promotes homophilic cell adhesion. Inhibition of VE-cadherin by the blocking monoclonal antibody (mAb) BV13 inhibited angiogenesis and tumor growth in vivo. However, this effect was accompanied by a marked increase in lung and heart permeability. In the present paper, we characterize a different VE-cadherin mAb (BV14) that is able to inhibit angiogenesis without affecting vascular permeability. In vitro studies show that BV14, in contrast to BV13, did not increase paracellular permeability of endothelial monolayers and did not disrupt VEcadherin clusters at junctions. However, both antibodies could inhibit formation of vascularlike structures in collagen gels and increase migration of endothelial cells into wounded areas. In vivo, BV14 and BV13 were equally active in inhibiting angiogenesis in the mouse cornea and in reducing the growth of hemangioma and C6 glioma. In contrast to BV13, BV14 did not change vascular permeability in all the organs tested and at any dose used. BV14 and BV13 bind to VE-cadherin extracellular repeats EC4 and EC1, respectively. We propose that, in
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