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.

Decoding microglia responses to psychosocial stress reveals blood-brain barrier breakdown that may drive stress susceptibility

“…We mined published microarray data sets to further define phenotypes in the present data using Gene Set Enrichment Analysis (GSEA) 87 ( http://broadinstitute.org/GSEA ) according to methods described previously 88 . The GSEA algorithm computes a ranked list of all genes from a microarray comparison between two conditions and identifies whether individual members of an a priori functionally defined gene set (black vertical bars) are enriched at either the top (red area) or bottom of the ranked genes (blue area) or randomly distributed across the whole ranked gene list, using a modified Kolmogorov-Smirnov statistic and generating an enrichment score.…”

Candesartan ameliorates brain inflammation associated with Alzheimer's disease

“…In PD mouse model, ARB treatment protected from dopaminergic neurons death, reduced motor deficits, and inhibited microglial activation . Candesartan (a blood‐brain barrier–entering ARB) reversed the neurotoxic effects of AT1R overstimulation in animal models of systemic inflammation . Candesartan, subcutaneous administered, to LPS‐injected hypertensive or normotensive rats decreased the LPS‐induced gliosis in the brain parenchyma .…”

“…Candesartan, subcutaneous administered, to LPS‐injected hypertensive or normotensive rats decreased the LPS‐induced gliosis in the brain parenchyma . Interestingly, a recent study indicated a great neuroprotective potential for candesartan in AD as it affected the expression of hundreds of genes in AD patients’ cortex and hippocampus …”

The Renin-Angiotensin System in the Central Nervous System and Its Role in Blood Pressure Regulation

“…These findings resulted in considerable advances in utilizing brain RAS blockade or RAS modulation as a therapeutic strategy to treat diseases beyond neurogenic hypertension. This is specifically relevant in stroke and cerebrovascular diseases, Alzheimer's disease, cognitive dysfunction, Parkinson disease, aging, and others [107][108][109][110][111][112][113][114][115]. Numerous other new molecules or administration routes to target the brain RAS are currently under investigation.…”