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Several sources of data suggest that some species of herpes virus contribute to the development of Alzheimer's disease, according to a new study. This new work brings science closer to clarifying the mechanisms by which infectious agents can play an important role in the disease.
With more people living at a later age, it is increasingly necessary to clarify the risk factors and mechanisms of Alzheimer's disease and use this information to find new ways to treat and prevent this terrible disease. Now, this first study of its kind involves another culprit in the pathway of Alzheimer's disease: the presence of viruses in the brain.
Scientists at the Arizona State University Center for Neurodegenerative Disease Research and their colleagues at the Icahn School of Medicine at Mount Sinai used extensive sets of data from clinically and neuropathologically characterized brain donors. sophisticated tools for massive data analysis. both inherited genes and those that are preferentially activated or deactivated in the brains of people with Alzheimer's disease.
Complete sequencing of the exome
The team capitalized on the DNA and RNA sequencing data of 622 brain donors with the clinical and neuropathological features of Alzheimer's disease and 322 brain donors without the disease – data generated by the sponsored fast-track partnership by the NIH for Alzheimer's disease.
The "whole exome" DNA sequencing was used to provide detailed information on genes inherited from each person. Sequencing of RNA from multiple brain regions has been used to provide detailed information on genes that are expressed differently in donors with and without the disease.
Clinical assessments conducted before the participants' deaths provided detailed information on their cognitive decline trajectory, and post-mortem neuropathological assessments provided relevant neuropathological information, including the severity of plaque and amyloid tangles, the cardinal features of the disease. d & # 39; Alzheimer's. Sophisticated computational tools have been used to develop a kind of large, unified image of the viral-AD nexus.
Big Data
The big data-based analyzes offer a particularly powerful approach for the exploration of diseases such as Alzheimer's disease, which involve many interdependent variables acting together in deeply complex systems.
In this study, researchers are exploring viral presence in six key brain regions known to be highly vulnerable to the ravages of AD. It is now accepted that adverse effects on these areas often precede the clinical diagnosis of the disease by several decades.
The study identifies high levels of human herpesvirus (HHV) 6A and 7 in brain samples showing signs of neuropathology of AD, compared with lower levels found in normal brains. In addition, through careful comparison of large sets of viral RNA and DNA with networks of human genes associated with Alzheimer's disease and signs of neuropathology, the study offers the first clues of the viral mechanisms that can trigger or exacerbate the disease.
The results, initially suggested from samples provided by Translational Genomics (Phoenix), were confirmed in Mount Sinai Brain Bank, and then replicated in samples from the Mayo Clinic Brain Bank, Rush Alzheimer's Disease Center. and Banner-Sun Health. Brain donation program and the body of the Research Institute.
Uninvited guests
According to Ben Readhead, lead author of the new study, the general goal of the researchers was to uncover the mechanisms of the disease, including those that could be targeted by repetitive or experimental drug therapies.
"We did not look for viruses, but the viruses screamed at us"
Readhead said. Although the study found a number of common viruses in normal aging brains, the viral abundance of two key viruses – HHV 6A and 7 – was greater in Alzheimer's brains. .
"We have been able to use a range of networked biology approaches to unravel how these viruses can interact with human genes that we know are relevant to Alzheimer's disease,"
Readhead said.
The nature and significance of viruses and other pathogens in the brain are currently topical in neuroscience, although exploration is still in its infancy. One of the main questions is whether these pathogens play an active and causal role in the disease or if they enter the brain simply as opportunistic passengers, taking advantage of the neuronal deterioration characteristic of the disease d & # 39; Alzheimer's.
"Previous studies on viruses and Alzheimer's disease have always been very indirect and correlative.But we have been able to perform a more sophisticated computational analysis using multiple levels of measured genomic information. directly from the affected brain tissue, this analysis has allowed us to identify how the viruses interact directly with known Alzheimer's genes, and I do not think we can answer the question of whether herpesviruses are a primary cause of Alzheimer's disease.But what is clear is that they disrupt and participate in networks that directly underlie the pathophysiology of Alzheimer's disease. " .
said Joel Dudley, associate professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai.
The hypothesis of the pathogen of Alzheimer's
The new study uses a networked biology approach to holistically integrate the molecular, clinical, and neuropathological features of AD with viral activity in the brain. Using techniques in bioinformatics, the study integrates high-throughput data into probabilistic networks that are postulated to account for associations between herpes viruses and the tell-tale effects of AD.
The networks described suggest that AD characteristics may appear as collateral damage caused by the brain's response to viral aggression.
Credit: Shireen Dooling for the Biodesign Institute at the ASU
According to the so-called pathogenesis of AD, the brain reacts to infection by engulfing viruses with amyloid beta protein (Aβ), sequestering invaders and preventing them from binding to cell surfaces and to insert their viral genetic load into healthy cells.
As explained Readhead,
"A number of viruses have seemed interesting.We have observed a key virus, the HHV 6A, which regulates the expression of a few genes and risk genes of MA known to regulate the treatment of amyloid, a key ingredient of the neuropathology of AD ".
Amyloid concentrations form characteristic plaques in the brain. These plaques, with neurofibrillary tangles formed by another protein, called tau, are the microscopic brain abnormalities used to diagnose Alzheimer's disease.
Both HHV 6A and 7 are common herpesviruses belonging to the genus Roseolovirus. Most people are exposed to it early in life.
The likely route of entry for these viruses is the nasopharyngeal mucosa. The higher abundance of these viruses in AD brains can trigger an immune cascade leading to deterioration and cell death or acting in other ways to promote AD.
Leverage converging results
The results of human brain tissue have been supplemented by studies in mice. Here, the researchers examined the effect of depletion of miR155, a small extract of RNA (or micro RNA) that is an important regulator of the innate and adaptive immune system.
The results showed increased deposition of amyloid plaques in miR155-depleted mice, coupled with behavioral changes. As noted by the authors, HHV 6A is known to deplete miR155, lending more weight to a viral contribution to AD.
"This study illustrates the promise of leveraging human brain samples, new methods for analyzing large data, convergent results of experimental models, and intensive collaborative approaches in the scientific understanding of Alzheimer's disease." and the discovery of new treatments. We are excited to take advantage of this approach to help scientific understanding, treatment and prevention of Alzheimer's disease and other neurodegenerative diseases. "
said co-author of the study, Eric Reiman, executive director of the Banner Alzheimer's Institute and professor of neuroscience at the State University of Arizona.
Meanwhile, Alzheimer's disease continues its devastating trajectory. Among the many challenges facing researchers, there is the fact that the first effects of the disease on vulnerable areas of the brain occur 20 or 30 years before memory loss, confusion, mood changes and other clinical symptoms.
Without cure or effective treatment, Alzheimer's disease is expected to hit a new victim in the United States every 33 seconds by the mid-century and costs are expected to exceed $ 1 trillion per year.
The study does not suggest that Alzheimer's disease is contagious. But if viruses or other infections play a role in the pathogenesis of Alzheimer 's disease, this could allow researchers to find new antiviral or immune therapies to fight the disease, even before the disease. appearance of symptoms.
Ben Readhead et al
A multi-scale analysis of independent Alzheimer cohorts reveals the disruption of molecular, genetic, and clinical networks by the human herpesvirus
Neuron DOI: https://doi.org/10.1016/j.neuron.2018.05.023
Top Image: Shireen Dooling for the Biodesign Institute at the ASU
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