Dr Itzhaki tells me that there is no interest in funding this research and that her team may cease to exist in the near future. If you read the summary of the research (below) you may, like me, be flabbergasted.
Role of a virus in Alzheimer’s disease, and prospects of treatment with antiviral agents
Almost 18 million people worldwide suffer from Alzheimer’s disease (AD) and unfortunately, this figure will rise as longevity increases. The need for effective treatments is therefore extremely urgent. (Current treatments alleviate symptoms but do not prevent further deterioration.) Most AD researchers investigate the disease’s main characteristics – abnormal structures in brain called tangles and plaques which are probably important features of the disease; however, despite the vast amount of information gathered about the structures, the causes of their formation are unknown.
Our research, which has strongly implicated a common virus in the development of the disease, is completely original and offers a direct route to treatment: very effective and safe antiviral agents are available to combat the virus and thus to treat AD patients. It indicates also the future possibility of preventing the disease by vaccination against the virus in infancy.
The virus implicated in AD, herpes simplex virus type 1 (HSV1), is the one that causes cold sores. It infects most humans in infancy and thereafter remains in the body in latent (i.e., dormant) form within the peripheral nervous system (the part of the nervous system other than the brain and spinal cord). From time to time – for example if the person is stressed – the virus becomes activated and in some people it then causes cold sores..
We found that the virus is present also in brain, in many elderly people, that it confers a strong risk of AD when in the brain of people who have a specific genetic factor (APOE-e4), and that it does become activated, perhaps recurrently, in brain. The likelihood of developing AD is 12 times greater for APOE-e4 carriers with HSV1 in brain than for those with neither factor.
Subsequently, we linked HSV1 directly to AD plaques and tangles. We discovered that the viral DNA is located very specifically in plaques. We found also that the main component of plaques, beta amyloid (Aβ), accumulates in HSV1-infected cell cultures and in the brains of infected mice. Taken together, these results suggest that HSV1 is a cause of toxic amyloid products and plaques. We have shown too that the main component of tangles – hyperphosphorylated tau – accumulates in HSV1-infected cell cultures. Studies by other groups have confirmed the HSV1-induced formation of Aβ and abnormal tau. Possibly, infected cells produce Aβ and abnormal tau as part of their “innate” immune system, in an attempt to protect against HSV1, but eventually these molecules are over-produced and then cause damage. Alternatively, cells may produce them because they are needed by HSV1 for its replication (the virus subverts the cell’s machinery to produce, in general, only such proteins).
We propose that HSV1 enters the brain in the elderly as their immune systems decline, establishes a latent infection from which it is repeatedly reactivated by events such as stress, immunosuppression, and brain inflammation induced by systemic infection, and that repeated activation causes cumulative damage* and eventually AD, in APOE-e4 carriers. (Other studies of ours support the concept that genetic factors can determine the severity of a microbial disease in showing that in the case of several diverse microbes, APOE affects outcome of infection. Probably significantly, we found APOE-e4 to be a risk for cold sores.) The mechanism might involve up-regulation of enzymes involved in Aβ formation and, via the known inhibitory effect the virus has on autophagy, prevention of abnormal protein degradation. Aβ might be produced as part of the cell’s defence response, initially entombing the agent and thereby preventing further damage to the host, but eventually, through overproduction, resulting in toxicity via oligomer formation. Infected cells, after suffering severe structural damage, die and disintegrate, releasing amyloid aggregates which develop into plaques after other components of dying cells are deposited on them. Presumably, in APOE-ε4 carriers, AD develops either as a consequence of greater HSV1-induced formation of toxic Aβ products, or as a direct consequence of virus-induced cell death or inflammation.
Our data suggest that antiviral agents might be used for treating AD. Currently available antiviral agents act by targeting replication of HSV1 DNA, and so we considered that they might be successful in treating AD only if the accumulation of Aβ and P-tau caused by HSV1 occurs at or after the stage at which viral DNA replication occurs. If these proteins are produced independently of HSV1 replication, antivirals might not be effective. We investigated this and found that treatment of HSV1-infected cells with acyclovir, the most commonly used anti-HSV antiviral agent, and also with two other anti-HSV antivirals, does indeed decrease Aβ and P-tau, as well as decreasing HSV1 replication (as expected).
*This is supported by a study by a prominent US virologist who has recently found that repeated activation of HSV1 in infected mice over a long period of time causes the formation of lesions in their brains