Alzheimer's disease (AD) is pathologically defined by presence of intracellular neurofibrillary tangles and extracellular amyloid plaques comprised of amyoid-β (Aβ) peptides. Despite local ...recruitment of brain microglia to sites of amyloid deposition, these mononuclear phagocytes ultimately fail at restricting β-amyloid plaque formation. On the other hand, it is becoming increasingly clear that professional phagocytes from the periphery possess Aβ clearance aptitude. Yet, in order to harness this beneficial innate immune response, effective strategies must be developed to coax monocytes/macrophages from the periphery into the brain. It has previously been suggested that Aβ 'immunotherapy' clears cerebral Aβ deposits via mononuclear phagocytes, and recent evidence suggests that targeting transforming growth factor-β-Smad 2/3 signaling and chemokine pathways such as Ccr2 impacts blood-to-brain trafficking of these cells in transgenic mouse models of AD. It has also been shown that the fractalkine receptor (Cx3cr1) pathway plays a critical role in chemotaxis of mononuclear phagocytes toward neurons destined for death in AD model mice. In order to translate these basic science findings into AD treatments, a key challenge will be to develop a new generation of pharmacotherapeutics that safely and effectively promote recruitment of peripheral amyloid phagocytes into the AD brain.
Abstract Amyloid-β (Aβ) immunization efficiently reduces amyloid plaque load and memory impairment in transgenic mouse models of Alzheimer's disease (AD). Active Aβ immunization has also yielded ...favorable results in a subset of AD patients. However, a small percentage of patients developed severe aseptic meningoencephalitis associated with brain inflammation and infiltration of T-cells. We have shown that blocking the CD40–CD40 ligand (L) interaction mitigates Aβ-induced inflammatory responses and enhances Aβ clearance. Here, we utilized genetic and pharmacologic approaches to test whether CD40–CD40L blockade could enhance the efficacy of Aβ1–42 immunization, while limiting potentially damaging inflammatory responses. We show that genetic or pharmacologic interruption of the CD40–CD40L interaction enhanced Aβ1–42 immunization efficacy to reduce cerebral amyloidosis in the PSAPP and Tg2576 mouse models of AD. Potentially deleterious pro-inflammatory immune responses, cerebral amyloid angiopathy (CAA) and cerebral microhemorrhage were reduced or absent in these combined approaches. Pharmacologic blockade of CD40L decreased T-cell neurotoxicity to Aβ-producing neurons. Further reduction of cerebral amyloidosis in Aβ-immunized PSAPP mice completely deficient for CD40 occurred in the absence of Aβ immunoglobulin G (IgG) antibodies or efflux of Aβ from brain to blood, but was rather correlated with anti-inflammatory cytokine profiles and reduced plasma soluble CD40L. These results suggest CD40–CD40L blockade promotes anti-inflammatory cellular immune responses, likely resulting in promotion of microglial phagocytic activity and Aβ clearance without generation of neurotoxic Aβ-reactive T-cells. Thus, combined approaches of Aβ immunotherapy and CD40–CD40L blockade may provide for a safer and more effective Aβ vaccine.
Reactive microglia have been suggested to play a role in the Alzheimer's disease (AD) process, and previous studies have shown that expression of CD45, a membrane-bound protein-tyrosine phosphatase ...(PTP), is elevated in microglia in AD brain compared with controls. To investigate the possible role of CD45 in microglial responsiveness to beta-amyloid (Abeta) peptides, we first co-treated primary cultured microglia with a tyrosine phosphatase inhibitor potassium bisperoxo (1,10-phenanthroline) oxovanadate (phen), 5 micrometer and freshly solubilized Abeta peptides (1000 nm). Data show synergistic induction of microglial activation as evidenced by tumor necrosis factor alpha (TNF-alpha) production and nitric oxide (NO) release, both of which we show to be dependent on activation of p44/42 mitogen-activated protein kinase (MAPK). Furthermore, co-treatment with phen and Abeta peptides results in microglia-induced neuronal cell injury. Stimulation of microglial CD45 by anti-CD45 antibody markedly inhibits these effects via inhibition of p44/42 MAPK, suggesting that CD45 is a negative regulator of microglial activation. Accordingly, primary cultured microglia from CD45-deficient mice demonstrate hyper-responsiveness to Abeta, as evidenced by TNF-alpha release, NO production, and neuronal injury after stimulation with Abeta peptides. As a validation of these findings in vivo, brains from a transgenic mouse model of AD transgenic Swedish APP-overexpressing (Tg APP(sw)) mice deficient for CD45 demonstrate markedly increased production of TNF-alpha compared with Tg APP(sw) mice. Taken together, these results suggest that therapeutic agents that stimulate the CD45 PTP signaling pathway may be effective in suppressing microglial activation associated with AD.
Genetic association studies investigating the role of the +118A allele of the human mu-opioid receptor gene in risk for alcohol dependency have produced inconsistent findings, possibly because of the ...failure to recognize sampling methodology difficulties inherent in association studies of polygenic disorders. We examined the frequency of the AA genotype and A allele in several groups of substance-dependent cases, unrestricted controls, and super controls screened for the use of alcohol and cigarettes. Our findings and analyses suggest that the OPRM1 +118 polymorphism is a general risk gene for substance dependence, but is not specific to a particular substance. The nature of the conferred risk is likely to be in use of multiple substances, but it is not yet determined if the risk could be expressed in severity of use of any particular substance. The contribution of the gene to risk for substance dependence is small, and is detected most easily in studies that use control samples that are screened for all forms of substance dependence.
Reactive oxygen species (ROS) are thought to be primary in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). However, as direct evidence of ROS has not yet been demonstrated ...in cerebral vasospasm, we sought to substantiate superoxide anion (.O(2)(-)) generation in the subarachnoid space after SAH using a modification of Karnovsky's manganese/diaminobenzidine (Mn(2+)/DAB) technique.
SAH or sham operation was induced according to a 2-hemorrhage model in a total of 24 beagle dogs. On day 2 or 7 after SAH or sham operation, dogs were intrathecally infused with buffer containing Mn(2+) and DAB, and the brain stem was prepared for light and electron microscopy. Possible colocalization of ferrous (Fe(2+)) or ferric (Fe(3+)) iron ions with.O(2)(-) was also examined with the use of Turnbull blue or Berlin blue staining, respectively.
Light microscopy revealed amorphous, amber deposits within the subarachnoid hematoma, the periarterial space, and the tunica adventitia of the basilar artery on days 2 and 7 after SAH.O(2)(-) deposits were eliminated by addition of superoxide dismutase or exclusion of either Mn(2+) or DAB from the perfusate, confirming the specificity of the reaction. These deposits were colocalized with blue reaction deposits indicating Fe(2+) and Fe(3+). Within the subarachnoid space,.O(2)(-) indicating electron-dense fine granules were preferentially located around degenerated erythrocytes and, secondarily, infiltrating macrophages and neutrophils.
We show direct evidence for enhanced production of.O(2)(-) and Fe(2+)/Fe(3+) iron ions in the subarachnoid space after SAH, lending further support to the pathogenic role of ROS in cerebral vasospasm after SAH.
Several independent studies have reported that loci on chromosome 10 are associated/linked with Alzheimer's disease (AD), including a family-based study demonstrating an association between the ...marker D10S583 and AD. We have examined the D10S583 polymorphic marker and apolipoprotein E (APOE) gene in a case–control study. We observed the expected association of the APOE allele ε4 with AD, and an inverse association between the D10S583 allele 209 and AD. These data support the original findings that suggest the presence of a candidate gene for AD in this region of chromosome 10. The nearby insulin degrading enzyme gene has been previously proposed as a candidate gene; however, a number of other putative candidate genes are also located in this region. The ongoing investigation of the genetic source of association and linkage in this region is clearly warranted.
The T-helper-cell 1 and 2 (T(H)1 and T(H)2) pathways, defined by cytokines interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), respectively, comprise two alternative CD4+ T-cell fates, with ...functional consequences for the host immune system. These cytokine genes are encoded on different chromosomes. The recently described T(H)2 locus control region (LCR) coordinately regulates the T(H)2 cytokine genes by participating in a complex between the LCR and promoters of the cytokine genes Il4, Il5 and Il13. Although they are spread over 120 kilobases, these elements are closely juxtaposed in the nucleus in a poised chromatin conformation. In addition to these intrachromosomal interactions, we now describe interchromosomal interactions between the promoter region of the IFN-gamma gene on chromosome 10 and the regulatory regions of the T(H)2 cytokine locus on chromosome 11. DNase I hypersensitive sites that comprise the T(H)2 LCR developmentally regulate these interchromosomal interactions. Furthermore, there seems to be a cell-type-specific dynamic interaction between interacting chromatin partners whereby interchromosomal interactions are apparently lost in favour of intrachromosomal ones upon gene activation. Thus, we provide an example of eukaryotic genes located on separate chromosomes associating physically in the nucleus via interactions that may have a function in coordinating gene expression.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by deposition of beta-amyloid (Abeta) peptides as senile plaques in the brain. Recent studies suggest ...that green tea flavonoids may be used for the prevention and treatment of a variety of neurodegenerative diseases. Here, we report that (-)-epigallocatechin-3-gallate (EGCG), the main polyphenolic constituent of green tea, reduces Abeta generation in both murine neuron-like cells (N2a) transfected with the human "Swedish" mutant amyloid precursor protein (APP) and in primary neurons derived from Swedish mutant APP-overexpressing mice (Tg APPsw line 2576). In concert with these observations, we find that EGCG markedly promotes cleavage of the alpha-C-terminal fragment of APP and elevates the N-terminal APP cleavage product, soluble APP-alpha. These cleavage events are associated with elevated alpha-secretase activity and enhanced hydrolysis of tumor necrosis factor alpha-converting enzyme, a primary candidate alpha-secretase. As a validation of these findings in vivo, we treated Tg APPsw transgenic mice overproducing Abeta with EGCG and found decreased Abeta levels and plaques associated with promotion of the nonamyloidogenic alpha-secretase proteolytic pathway. These data raise the possibility that EGCG dietary supplementation may provide effective prophylaxis for AD.
West Nile virus (WNV), a mosquito-borne single-stranded (ss)RNA flavivirus, causes human disease of variable severity. We investigated the involvement of Toll-like receptor (Tlr) 3, which recognizes ...viral double-stranded (ds)RNA, on WNV infection. Tlr3-deficient (Tlr3(-/-)) mice were more resistant to lethal WNV infection and had impaired cytokine production and enhanced viral load in the periphery, whereas in the brain, viral load, inflammatory responses and neuropathology were reduced compared to wild-type mice. Peripheral WNV infection led to a breakdown of the blood-brain barrier and enhanced brain infection in wild-type but not in Tlr3(-/-) mice, although both groups were equally susceptible upon intracerebroventricular administration of the virus. Tumor necrosis factor-alpha receptor 1 signaling is vital for blood-brain barrier compromise upon Tlr3 stimulation by dsRNA or WNV. Collectively, WNV infection leads to a Tlr3-dependent inflammatory response, which is involved in brain penetration of the virus and neuronal injury.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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