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

Abdel G. Elkahloun

Juan M. Saavedra

Roman Hafko

PubMed

Pathways associated with genes preferentially expressed in cerebrovascular endothelial cells. Figure S4 notes pathways associated with genes that are upregulated in Alzheimer's disease and downregulated by candesartan in our neuronal cultures and are more expressed in endothelial cells. Genes are red in the outer circle and pathways are in orange in the inside circle. Orange dotted lines are for positive effect and blue dotted lines are for negative effect of the gene on the pathway. (PDF 940 kb

Abdel Elkahloun (208112)

Roman Hafko (429007)

Juan Saavedra (3580244)

The Francis Crick Institute

Additional file 10: Figure S4. of An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimerâs disease

Candesartan prevents glutamate-induced inflammation 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, glutamate vs. control; # p < 0.05, ## p < 0.01, candesartan + glutamate vs glutamate. (PDF 98 kb

Additional file 4: Figure S2. of An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease

Springer - Publisher Connector

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

Candesartan prevents glutamate-induced inflammation 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 < 0.01glutamate vs. control; # p < 0.05, ## p < 0.01, candesartan + glutamate vs glutamate. (PDF 62 kb

Additional file 5: Figure S3. of An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease

Abstract
                Background
                Alzheimer’s disease is the most frequent age-related dementia, and is currently without treatment. To identify possible targets for early therapeutic intervention we focused on glutamate excitotoxicity, a major early pathogenic factor, and the effects of candesartan, an angiotensin receptor blocker of neuroprotective efficacy in cell cultures and rodent models of Alzheimer’s disease. The overall goal of the study was to determine whether gene analysis of drug effects in a primary neuronal culture correlate with alterations in gene expression in Alzheimer’s disease, thus providing further preclinical evidence of beneficial therapeutic effects.
              
                Methods
                Primary neuronal cultures were treated with candesartan at neuroprotective concentrations followed by excitotoxic glutamate amounts. We performed genome-wide expression profile analysis and data evaluation by ingenuity pathway analysis and gene set enrichment analysis, compared with alterations in gene expression from two independent published datasets identified by microarray analysis of postmortem hippocampus from Alzheimer’s disease patients. Preferential expression in cerebrovascular endothelial cells or neurons was analyzed by comparison to published gene expression in these cells isolated from human cortex by laser capture microdissection.
              
                Results
                Candesartan prevented glutamate upregulation or downregulation of several hundred genes in our cultures. Ingenuity pathway analysis and gene set enrichment analysis revealed that inflammation, cardiovascular disease and diabetes signal transduction pathways and amyloid β metabolism were major components of the neuronal response to glutamate excitotoxicity. Further analysis showed associations of glutamate-induced changes in the expression of several hundred genes, normalized by candesartan, with similar alterations observed in hippocampus from Alzheimer’s disease patients. Gene analysis of neurons and cerebrovascular endothelial cells obtained by laser capture microdissection revealed that genes up- and downregulated by glutamate were preferentially expressed in endothelial cells and neurons, respectively.
              
                Conclusions
                Our data may be interpreted as evidence of direct candesartan neuroprotection beyond its effects on blood pressure, revealing common and novel disease mechanisms that may underlie the in vitro gene alterations reported here and glutamate-induced cell injury in Alzheimer’s disease. Our observations provide novel evidence for candesartan neuroprotection through early molecular mechanisms of injury in Alzheimer’s disease, supporting testing this compound in controlled clinical studies in the early stages of the illness.
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Crossref

Alzheimer s Research & Therapy

Additional file 6: Table S3. of An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease

https://figshare.com/articles/Additional_file_5_Figure_S3_of_An_integrative_genome-wide_transcriptome_reveals_that_candesartan_is_neuroprotective_and_a_candidate_therapeutic_for_Alzheimer_s_disease/4468346

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

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The Francis Crick Institute

The Francis Crick Institute

Springer - Publisher Connector

The Francis Crick Institute

Springer - Publisher Connector

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The Francis Crick Institute