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Manchester Institute for Collaborative Research on Ageing

Professor Ruth Itzhaki speaks on her research into the potential links between Alzheimer's disease and the herpes simplex virus type 1 (HSV1)

16 November 2018

Over 30 million people worldwide suffer from Alzheimer’s disease and unfortunately, this figure will rise as longevity increases, so the need for effective treatments is extremely urgent.

Current treatments, at best, alleviate symptoms but do not prevent further deterioration. Our research has strongly implicated a common virus in the development of the disease, indicating a direct route to treatment: very effective and safe antiviral agents are available to combat the virus and thus to treat AD patients. They indicate also the future possibility of preventing the disease by vaccination against the virus in infancy.

The virus implicated in Alzheimer's disease, herpes simplex virus type 1 (HSV1), is the one that causes cold sores.  It infects most humans and thereafter remains lifelong in the body in latent (i.e., dormant) form within the peripheral nervous system (PNS - the part other than the brain and the spinal cord).  Occasionally, if the person is stressed, the virus becomes activated and in some people it then causes cold sores.

We discovered in 1991 that in many elderly people, HSV1 is present also in brain, and we later showed in 1997 that it confers a strong risk of Alzheimer's disease when in the brain of people who have a specific genetic factor known as APOE4. The virus can become active in brain, perhaps recurrently - thereby very probably leading to cumulative damage. The likelihood of developing  Alzheimer's disease is 12 times greater for APOE4 carriers who have HSV1 in brain than for those with neither factor. Subsequently, we and others found that HSV1 infection of cell cultures causes formation of the main components, called beta amyloid and P-tau respectively, of the abnormal structures characteristic of  Alzheimer's disease, known as plaques and tangles.

We propose that HSV1 is a major contributory factor for Alzheimer's disease, that it enters the brain in the elderly as their immune system declines during ageing. It then establishes a latent (dormant) infection there, from which it is reactivated by events such as stress, immunosuppression, and brain inflammation induced by infection by other microbes. Reactivation leads to direct viral damage in infected cells and to viral-induced inflammation. We suggest that repeated activation causes cumulative damage, leading eventually to Alzheimer's disease in people with an APOE4 allele.  Presumably, in APOE4 carriers, Alzheimer's disease develops in brain because of greater HSV1-induced formation of toxic products, or lesser repair of damage.

The data suggest that antiviral agents might be used for treating Alzheimer's disease. The main antiviral agents, which are very safe, act by preventing the formation of new viruses, thereby limiting viral damage. We found that the antiherpes antiviral drug acyclovir (ACV), blocks HSV1 DNA replication, and reduces levels of beta amyloid and of P-tau caused by HSV1 infection of cell cultures. Two recent publications (in the journal Neuron) were widely publicised, one of them implicating two other types of herpes virus, HHV6 and HHV7, in the disease, and the other showing that beta amyloid might have a protective role. However, all of the above studies show just an association between herpes virus and AD but cannot prove that the virus is an actual cause.

Probably the only way to prove that a microbe is a cause of a disease is to demonstrate  that a occurrence of the disease is greatly reduced either by targeting the microbe with a very specific anti- microbial agent, or by very specific vaccination against the microbe. Excitingly, successful prevention of Alzheimer's disease by use of specific anti-herpes agents has now been demonstrated in a large-scale population study in Taiwan. Hopefully, information in other countries, if available, will yield similar results. Hopefully also, funding will be provided  in the UK for carrying out  clinical trials of antiherpes antiviral agents for treating Alzheimer's disease patients.

 

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