" Molecular Neurobiology and Brain Biochemistry. "

Molecular Neurobiology and Brain Biochemistry


Professor R F Itzhaki
Molecular Neurobiology Laboratory
HERPES VIRUS IN BRAIN: A RISK FACTOR IN ALZHEIMER'S DISEASE

Over 300, 000 people suffer from Alzheimer's disease (AD) in the UK. Because of the increasing number of people surviving to old age, the problem will worsen, and in fact it is predicted that half a million people will be affected by AD by the year 2000. Nearly all AD patients have the non-inherited form of the disease, in which the only known risk factors are age, Down's syndrome and probably head injury, though recently an inherited susceptibility factor, was found - the type 4 form ('allele') of the gene or apolipoprotein E (apoE), a protein involved in transport of cholesterol, and which appears to be involved also in repair of tissue damage. However, an apoE4 allele is neither sufficient nor essential or development of the disease: some people who develop the disease do not have an apoE4 allele and some who do have an E4 allele do not develop the disease. Other genetic or environmental factors - very robably several rather than a single one - must therefore be involved also, acting as risk factors perhaps in combination with an apoE4 allele, or possibly quite independently. We are examining the possible role of the environmental factor, herpes simplex type 1 virus (HSV1), in the disease.

HSV1 was suggested as a possible risk factor in AD many years ago. However, the first question that needed to be answered was whether or not it was ever present in human brain, and this was totally unanswered by investigations in various labs. In contrast, it has long been known that the virus is harboured by nearly all adults in their peripheral nervous system (PNS), the part of the nervous system other than the brain and spinal cord, and in some people - for previously unknown reasons - it causes cold sores (herpes labialis) from time to time. We decided to use the ultra-sensitive technique known as PCR to search for the virus in brain. We have thus shown that virus DNA is in fact present in the brain of many elderly normal people and many AD patients, and we have suggested that it might cause more severe damage in brainof those destined to develop AD than in elderly normals because of a difference between the two groups of people either in their genetic characteristics or in the characteristics of the virus. We have now found that there is indeed a difference - a striking correlation - in that AD patients who harbour the virus in brain are far more likely than those who do not harbour it - and far more likely than normals, both virus-positive and virus-negative normals - to possess an apoE4 allele. We therefore propose that HSV1 in brain together with possession of an apoE4 allele confers a high risk of developing the disease whereas either factor on its own does not do so. (Our results show that alternative explanations - either that AD sufferers or that apoE4 possessors are more susceptible to HSV1 infection - can be discounted.)

On the basis that an analogous situation might occur in the PNS, we then decided to examine the apoE genotypes of cold sore sufferers. We found that a far higher proportion of sufferers than of non-sufferers are apoE4 possessors. This provides strong and independent support for our hypothesis that the combination of the environmental factor, HSV1, and the inherited factor is particularly damaging in the nervous system.

The virus (when present in brain) is the first environmental risk factor to be implicated definitely in AD (and the apoE4 allele is the first genetic factor to be found in cold sores);further, AD is the first brain disease in which an environmental risk factor acting with an inherited susceptibility factor has been identified. Our findings point to the future possibility of prevention of the disease by immunisation against the virus, or of retardation of the disease by the use of anti-viral agents (especially in apoE4 possessors).


The Team:

Ruth Itzhaki 0161 200 3879
Curtis Dobson 2423
Matthew Wozniak 2423
Suzanne Shipley 2423
Ann Cookson 2423










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