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Herpesvirus infections may have a pathogenic link to Alzheimer’s disease

Publish date: June 21, 2018

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Does herpesvirus join the list of infective degenerative brain diseases?

The study by Readhead and colleagues is a scientific tour de force and is likely to elevate the infective hypothesis to a greater height than ever before and deservedly so. Still, the findings are puzzling, at least to this relative virologic novice.

The relationship of infective agents with seemingly degenerative brain diseases has been a complex puzzle that has led to at least two major discoveries. First was the description of a lifeform simpler than viruses, the prion and identification of the human PrP gene that when mutated is the cause of familial Creutzfeldt-Jakob disease (CJD), which can also be transmitted from human to human (or human to monkey) via tissue transplants.

Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic in Scottsdale, Ariz., and associate director and clinical core director of Mayo’s Alzheimer’s Disease Center.

Dr. Richard J. Caselli

Second is the concept of a brain microbiome that when disrupted by certain immunosuppressive agents can give rise to progressive multifocal leukoencephalopathy (PML). Viruses live in our brain, normally under control, until something tips the scales in their favor. The time course of both CJD and PML is relatively rapid with few people surviving more than a year, and very unlike the far more slowly progressive course of Alzheimer’s disease whose symptomatic stage can last over a decade and whose preclinical stage may be more than 20 years, according to some studies. The topography of early-stage Alzheimer’s disease bears a striking resemblance to another herpesvirus that the authors did not identify, herpes simplex virus 1, which is the most common cause of viral encephalitis and is limbotropic, targeting the medial temporal lobe and adjacent structures very much like Alzheimer’s disease. Yet evidence relating HSV1 to Alzheimer’s disease has not been conclusive.

The data provided by Readhead and colleagues are compelling, however, and unquestionably deserve further attention. Where this will lead is still too early to tell, but given the failure of existing paradigms to translate into meaningful disease-modifying therapies, we have new reason to hope that such a therapy may yet be possible in our lifetime.

Richard J. Caselli, MD, is a professor of neurology at the Mayo Clinic Arizona in Scottsdale and is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center.


 

FROM NEURON

multiple regions, and Braak stage, a measure of neurofibrillary tangles.

Another investigation looked at the fractions of the four major brain cells (neurons, astrocytes, microglia, and endothelial cells) and their relationship to viral RNA. HHV-6a was associated with decreases in the neuronal content of fractions from multiple brain regions, and in all four datasets.

Dr. Haure-Mirande and the team also studied a mouse model lacking the virus-suppressing microRNA-155 molecule and crossed this with one of the most commonly used AD research strains that overexpresses human amyloid precursor protein and develops brain amyloidosis. At 4 months, these mice had larger, more frequent amyloid plaques than the standard amyloidosis mice. Cortical RNA sequencing revealed overlap between upregulated genes in the microRNA-155 knockout mice and the HHV-6a–upregulated genes in human brains.

“These findings support the view of microRNA-155 as a regulator of complex anti- and pro-viral actions, offer a mechanism linking viral activity with AD pathology, and support the hypothesis that viral activity contributes to AD,” the investigators wrote.

As Dr. Gandy said, while not definitive, the studies are tantalizing and lay a solid framework for further investigation. He is confident enough about the association to view HHV as a potential therapeutic target for AD.

“The first step is to find a way to detect the viruses in people. We do have our first antibody to recognize one of the viral proteins, so we’re about to test that on blood serum, blood cells, and spinal fluid, and we will also look for viral DNA in the blood cells. Potentially – way down the road – we might be able to conduct a trial using antivirals,” to see if treatment could slow, or prevent, Alzheimer’s progression.

“These are nice, discrete, testable hypotheses, which makes them attractive,” Dr. Gandy said, “but the truth could be different and is almost certainly a lot messier.”

Dr. Gandy has received research funding from Baxter and Amicus Therapeutics, and personal remuneration from Pfizer and DiaGenic.

SOURCE: Readhead B et al. Neuron. 2018 June 21. doi: 10.1016/j.neuron.2018.05.023 .

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