In laboratory neuronal cultures, an FDA-approved drug used to treat high blood pressure reduced cell damage often linked to Alzheimer’s disease, say researchers at Georgetown University Medical Center (GUMC) and the National Institutes of Health.
They say their work, published online Jan. 28 in the journal Alzheimer’s Research and Therapy, provides information supporting the potential effect of the drug candesartan — as well as other Angiotensin receptor blockers (ARBs) for the early treatment of Alzheimer’s disease.
“Our findings make sense in many ways,” says the study’s senior author Juan M. Saavedra, MD, from GUMC’s Department of Pharmacology and Physiology. “Hypertension reduces blood flow throughout the body and brain and is a risk factor of Alzheimer’s disease. Previous epidemiological studies found that Alzheimer’s progression is delayed in hypertensive patients treated with ARBs.”
Using neuronal cultures, the researchers explored the action of candesartan on the neurotoxic effects of exposure to excessive glutamate, a demonstrated injury factor in the early stages of Alzheimer’s disease.
The scientists found that candesartan prevented glutamate-induced neuronal death. They conducted in-depth gene analyses of the laboratory results, demonstrating that candesartan prevented neuronal inflammation and many other pathological processes, including alterations in amyloid metabolism, a hallmark of Alzheimer’s disease.
The study’s first author, Abdel G. Elkahloun, PhD, from the Comparative Genomics and Cancer Genetics Branch of the National Human Genome Research Institute, then compared gene expression in the neuronal cultures with published gene databases of autopsy samples from Alzheimer’s disease patients. “The correlations were impressive — the expression of 471 genes that were altered by excess glutamate in our cultures were also altered in brain autopsy samples from patients who suffered from Alzheimer’s disease. Candesartan normalized expression of these genes in our cultures,” Elkahloun says.
“We hypothesize that candesartan, or other members of the ARB group, may not only slow progression of Alzheimer’s but also prevent or delay its development,” Saavedra says.
The researchers say this work has immediate translational value, supporting testing candesartan, or other ARBs, in controlled clinical studies on patients at early stages of Alzheimer’s disease.
About this Alzheimer’s disease research
Roman Hafko, PhD, formerly of the National Institute of Mental Health, also contributed to this work and is an author of the paper.
Funding: The work was supported by grants from the National Institutes of Health including the National Human Genome Research Institute (MD 20892) and the National Institute of Mental Health (MH 002762-16). The authors report having no personal financial interests related to the study.
Source: Karen Teber – Georgetown University Medical Center Image Credit: The image is in the public domain Original Research: Full open access research for “An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease” by Abdel G. Elkahloun, Roman Hafko and Juan M. Saavedra in Alzheimer’s Research & Therapy. Published online January 28 2016 doi:10.1186/s13195-015-0167-5
An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease 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.
“An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer’s disease” by Abdel G. Elkahloun, Roman Hafko and Juan M. Saavedra in Alzheimer’s Research & Therapy. Published online January 28 2016 doi:10.1186/s13195-015-0167-5