Abstract
BackgroundAlzheimer’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.MethodsPrimary 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.ResultsCandesartan 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-015-0167-5) contains supplementary material, which is available to authorized users.
Highlights
Alzheimer’s disease is the most frequent age-related dementia, and is currently without treatment
In our search for novel compounds with neuroprotective effects against glutamate neurotoxicity, we focused in a class of compounds, the angiotensin receptor blockers (ARBs) or sartans, that effectively blocks the physiological AT1 receptor (AT1R) and the effects of angiotensin II, the main active factor of the renin–angiotensin system [13] both in the periphery and the brain [14]
We compared gene expressions altered in published Alzheimer’s disease patients with published analysis of predominant gene expression in human cerebrovascular endothelial cells and neurons obtained by laser capture microdissection from postmortem dorsolateral prefrontal cortex samples and we looked at the effect of candesartan on these gene signatures in our Cerebellar granule cell (CGC) study
Summary
Alzheimer’s disease is the most frequent age-related dementia, and is currently without treatment. Alzheimer’s disease is the most common age-related dementia and a major and increasing burden for our society [1] This disorder is currently without treatment, and therapies to ameliorate alterations in amyloid beta (Aβ) or tau metabolism, initiated too late in the disease course, have proven disappointing [2]. For this reason the search for early pathogenic mechanisms susceptible to therapeutic intervention is a medical necessity. Excessive production and release of glutamate, leads to neuronal injury and is a major pathogenic factor in many acute and chronic brain conditions, including Alzheimer’s disease [3, 8,9,10, 12]
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