Genomic regulation after CD40 stimulation in microglia: relevance to Alzheimer's disease.
ABSTRACT Key pathological processes in Alzheimer's disease (AD) include the accumulation of amyloid beta peptide (Abeta) which, in excess, triggers pathological cascades including widespread inflammation, partly reflected by chronic microglial activation. It has previously been suggested that CD40/CD40L interaction promotes AD like pathology in transgenic mice. Thus, amyloid burden, gliosis and hyperphosphorylation of tau are all reduced in transgenic models of AD lacking functional CD40L. We therefore hypothesized that cellular events leading to altered APP metabolism, inflammation and increased tau phosphorylation underlying these observations would be regulated at the genomic level. In the present report, we used the Affymetrix (GeneChip) oligonucleotide microarray U133A to gain insight into the global and simultaneous transcriptomic changes in response to microglia activation after CD40/CD40L ligation. As expected, regulation of elements of the NF-kappaB signaling, chemokine and B cell signaling pathways was observed. Taken together, our data also suggest that CD40 ligation in human microglia specifically perturbs many genes associated with APP processing.
SourceAvailable from: Bart Tummers[Show abstract] [Hide abstract]
ABSTRACT: The interaction between the transmembrane glycoprotein surface receptor CD40 expressed by skin epithelial cells (ECs) and its T cell-expressed ligand CD154 was suggested to exacerbate inflammatory skin diseases. However, the full spectrum of CD40-mediated effects by ECs underlying this observation is unknown. Therefore, changes in gene expression after CD40 ligation of ECs were studied by microarrays. CD40-mediated activation for 2 hours stimulated the expression of a coordinated network of immune-involved genes strongly interconnected by IL8 and TNF, while after 24 hours anti-proliferative and anti-apoptotic genes were upregulated. CD40 ligation was associated with the production of chemokines and the attraction of lymphocytes and myeloid cells from peripheral blood mononuclear cells (PBMCs). Thus, CD40-mediated activation of ECs resulted in a highly coordinated response of genes required for the local development and sustainment of adaptive immune responses. The importance of this process was confirmed by a study on the effects of human papilloma virus (HPV) infection to the EC's response to CD40 ligation. HPV infection clearly attenuated the magnitude of the response to CD40 ligation and the EC's capacity to attract PBMCs. The fact that HPV attenuates CD40 signalling in ECs indicates the importance of the CD40-CD154 immune pathway in boosting cellular immunity within epithelia.Journal of Investigative Dermatology accepted article preview online, 19 June 2014; doi:10.1038/jid.2014.262.Journal of Investigative Dermatology 06/2014; 134(12). DOI:10.1038/jid.2014.262 · 6.37 Impact Factor
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ABSTRACT: Abstract Alzheimer's Disease (AD) is a devastative neurodegenerative disorder with complex etiology. Neuroinflammation has been found to be an underlying cause of the disease although it demonstrates significant defensive role and renders the brain immunologically secured. This review focuses on the physiology and pathology of this crucial biological process and the diverse factors involved in and acting in a concerted manner to play a pivotal role either in the physiology or pathology of the disease. We used Pubmed, Pubmed Central, Medline databases for a period of 3 months. It also summarizes the recent advances in neuroinflammation in both in vitro and in vivo. This review eventually warrants further studies on animal models of AD to unravel the complete pathophysiology of the disease and also accentuates the burgeoning need to protect astrocytes which can become a substantial therapeutic avenue.The International journal of neuroscience 08/2013; DOI:10.3109/00207454.2013.831852 · 1.53 Impact Factor
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ABSTRACT: Estrogens have been found to improve memory and reduce risk of dementia, although conflicting results such as failure of estrogen replacement therapy for treatment of Alzheimer's disease (AD) also has been reported. Only recently, our published human brain studies showed a depletion of brain estrogen in women with AD, while other studies have demonstrated cognitive impairment believed to be caused by inhibition of endogenous estrogen synthesis in females. To investigate whether the shortage of brain estrogen alters the sensitivity of response to estrogen replacement therapy, we have used genetic and surgical animal models to examine the response of estrogen treatment in AD neuropathology. Our studies have shown that early treatment with 17β-estradiol (E2) or genistein could reduce brain amyloid levels by increasing Aβ clearance in both APP23 mice with genetic deficiency of aromatase (APP/Ar(+/-)), in which the brains contain nondetectable levels of estrogen, and in APP23 mice with an ovariectomy (APP/OVX), in which the brains still contain certain levels of estrogen. However, only APP/Ar(+/-) mice showed a great reduction in brain amyloid plaque formation after E2 or genistein treatment along with downregulation of β-secretase (BACE1) mRNA and protein expression. Our results suggest that early and long-term usage of E2 and/or genistein may prevent AD pathologies in a dependent manner on endogenous brain estrogen levels in aged females.Molecular Neurobiology 11/2012; DOI:10.1007/s12035-012-8377-3 · 5.29 Impact Factor