Team Reverses the Clinical Signs of Alzheimer’s Disease in Mice
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The World Health Organization estimates that more than 50 million people worldwide have dementia and that Alzheimer’s disease (AD) may contribute to 60–70% of cases. Despite garnering increasing attention from the scientific community, an incomplete understanding of the underlying molecular basis of Alzheimer’s disease has meant that it’s been difficult to translate basic research into novel treatments. Now, in a study published in Genome Medicine, Dr. Patrick Aloy, head of the structural bioinformatics and network biology laboratory at IRB Barcelona and colleagues report that they have successfully reversed the clinical signs of disease in mice by repurposing four existing drugs that are currently approved to treat high blood pressure and inflammation.
Technology Networks spoke to Patrick Aloy, to learn more about the study.
Laura Lansdowne (LL): What happens at each of the three stages of AD – onset, progression and advanced? Why was it important to know the stage of disease in the context of your study?
Patrick Aloy (PA): Basically, in this study, we tackled a double comparison: on the one hand between different AD mouse models and, on the other, between disease progression and healthy aging. There are many molecular players that change their regulation as AD progresses, but their regulation can also change as the mice get older, and an effective therapy should not focus on those. Instead, by comparing the dynamics of disease progression (onset, progression and advanced) to the physiological processes of aging (i.e., age-matched mice) we could discover modules that are indeed dysregulated in AD that are not just a consequence of aging. These are the ones that we sought to revert with chemical compounds.
LL: What are the key benefits to repurposing existing drugs?
PA: There are many advantages but, in this case, I would highlight only two. To conduct novel clinical trials on AD is a long and expensive process since we need to treat and follow up patients for many years. Not many pharmaceutical companies are willing to do it, since, unfortunately, the benefits of several drugs to date have been modest at best. Additionally, and perhaps more importantly, AD treatments must be chronic (i.e., for many years) and we need very safe drugs that have been vastly administered and followed up. And this is a condition that existing drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs) and anti-hypertensives, fulfill.
LL: Can you tell us more about the computational tool “Chemical Checker” that was used to search for promising drug compounds?
PA: The Chemical Checker (CC) is a resource that provides processed, harmonized and ready-to-use bioactivity signatures of small molecules. The CC divides data into five levels of increasing complexity, following the way we think of drug activity: a drug is often an organic molecule (chemistry) that interacts with one or several protein receptors (targets), triggering perturbations of biological pathways (networks) and eliciting phenotypic outcomes that can be measured in cell-based assays (cells) before delivery to patients (clinic). Our resource contains data on the effects exerted by about one million compounds in a wide range of biological settings, offering a rich portrait of the small molecule data available in the public domain. It also provides the opportunity to make queries that would be otherwise impossible using chemical information alone. These bioactivity signatures can be linked to biological experiments (i.e., differential gene expression), so that we can look for small molecules able to match or revert any given biological signatures caused, for instance, by the presence of certain disease-causing mutations. In this work, for instance, we looked for approved drugs able to revert the transcriptional and protein abundance changes caused by familiar AD mutations.
LL: Could you tell us more about the four drugs shown to be effective at reversing molecular signatures of AD in the mice?
PA: With the help of the CC, we could identify two main groups of drugs with the potential to revert AD signatures in mice – NSAIDs and anti-hypertensives. We then decided to test six of these compounds and, for novelty reasons, selected those that had not been tested before in the context of AD. We found that four of them (i.e., the NSAIDs dexketoprofen and etodolac and the anti-hypertensives penbutolol and bendroflumetiazide) had the potential to reverse the cognitive impairment observed in AD mice in a test known as novel object recognition, which basically assesses the curiosity of mice in front of a novel object. Additionally, all four compounds downregulated genes shown to be upregulated in AD with respect to healthy mice, and penbutolol could also, to some extent, lift the expression of genes downregulated in AD mice.
LL: In terms of next steps, what further research do you have planned?
PA: We work in a basic biomedical research environment, without access to patients, and thus our research focus is mainly preclinical. We will surely investigate further the potential mechanisms of action of these compounds in AD but will not make the leap to human subjects. Instead, we have published all our data in a completely open form, and hope that the dementia units in the hospital will consider our results. Indeed, there are already several epidemiological studies that point in the direction of our findings in human cohorts (i.e., populations that take NSAIDs or anti-hypertensives in a semi-chronic regime are less prone to develop AD).
Dr. Patrick Aloy was speaking with Laura Elizabeth Lansdowne, Managing Editor for Technology Networks.