An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease

IPA disease and/or function list for genes altered in glutamate versus glutamate + candesartan groups. (XLSX 67 kb

Abstract P161: Angiotensin Receptor Blockade Decreases Glutamate-induced Brain Inflammation

Chronic Kidney Disease (CKD) is very frequently associated with brain inflammation and cell injury leading to cognitive loss. At present a combined treatment of related kidney and brain injury has never been proposed. We focused on glutamate-induced excitotoxicity and neuronal inflammation, and on the effects of candesartan, a renoprotective Angiotensin Receptor Blocker (ARB) ameliorating hypertension and diabetes-induced kidney damage, and with accompanying neuroprotective efficacy. Primary cerebellar granule cells (CGC) were exposed to 100 μM glutamate and pre-treated for one hour with candesartan at neuroprotective concentrations (10 μM). Gene expression was quantified by qPCR. Candesartan significantly reduced glutamate-induced inflammation. Multiple group comparisons were performed by one-way ANOVA followed by Newman-Keuls post-test. Exposure to glutamate significantly reduced neuronal viability while up-regulating the expression of multiple genes on pro-inflammatory pathways, including Toll-like receptor 7 (Tlr7) and Nuclear factor of kappa light polypeptide gene enhancer in B-cells 2, p49/p100 (Nfkpb2). * p&lt;0.01, ** p&lt; 0.05, vs control; # p&lt; 0.01 vs glutamate. In all cases, pretreatment with candesartan completely prevented glutamate-induced neurotoxicity. Our results indicate that Angiotensin II receptor blockade with candesartan is strongly and directly neuroprotective, significantly ameliorating neuronal injury as a result of glutamate excitotoxicity. These results support the use of candesartan and other ARBs for the concomitant treatment of CKD and associated neuronal injury. </jats:p

Socio and Economic impacts of Hyperinflation on the Economy of the Weimar Republic

In my bachelor thesis I am focusing on the socio and economic impacts of hyperinflation on the economy of the Weimar Republic. In first chapters I am dealing with the analysis of long-term and short-term causes which led to hyperinflation. I am also taking into account German economic theory, manner of financing of the war in Germany and furthermore I am concentrating on the question of war indemnities and crisis in the Ruhr area. In the followingchapters I am dealing with the progress of hyperinflation and her economic, social and also political impacts. My aim is to confirm the hypothesis, in which I argue that hyperinflation had negative impact on economic and social situation inside the Weimar Republic. Thesis contributes to provide view of impacts of hyperinflation on German society in the year

Additional file 9: Table S9. of An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease

Complete GSEA analysis output of CGCs treated with glutamate and glutamate + candesartan and several inflammatory gene signatures and gene signature from postmortem Alzheimer’s disease patient and a mouse model of Alzheimer’s disease. (XLSX 4051 kb

Additional file 8: Table S5. of An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease

GSEA for the genes altered in glutamate versus glutamate + candesartan. Table S5 is a GSEA for the genes with altered expression in our glutamate versus glutamate + candesartan groups, and their correlation with several gene sets/signatures associated with specific molecular functions, diseases, INFG, IL6, TNF, LPS and neuronal functions. (PDF 5309 kb

Additional file 11: Table S6. of An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease

IPA of upstream regulators of genes preferentially expressed in cerebrovascular endothelial cells. Table S6 notes the upstream regulators of genes that are upregulated in Alzheimer’s disease and downregulated by candesartan in our neuronal cultures, and are of preferentially expressed in endothelial cells. (XLS 118 kb

Additional file 3: Figure S1. of An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease

Candesartan prevents glutamate-induced alterations in gene expression in rat CGCs. Alterations in gene expression revealed by microarray analysis were confirmed by qPCR. Results are means ± SEM of at least three independent experiments. *p < 0.05, **p < 0.01, ***p < 0.001, glutamate vs. control; # p < 0.05, ## p < 0.01, ### p < 00.1, Candesartan + glutamate vs glutamate. (PDF 74 kb

Additional file 14: Table S8. of An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease

IPA of upstream regulators of genes preferentially expressed in neurons. Table S8 notes the upstream regulators of genes that are downregulated in Alzheimer’s disease and upregulated by candesartan in our neuronal cultures, and are preferentially expressed in human neurons. (XLS 40 kb

Additional file 12: Table S7. of An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease

IPA of diseases and functions annotation of genes preferentially expressed in cerebrovascular endothelial cells. Table S7 notes the diseases and functions that are upregulated in Alzheimer’s disease and downregulated by candesartan and are preferentially expressed in cerebrovascular endothelial cells. (XLS 126 kb