Alzheimer Disease: Wozniak MA

Itzhaki RF, Wozniak MA. · Faculty of Life Science, The University of Manchester, Manchester, UK. · J Alzheimers Dis. · Pubmed #18487848 No free full text.

Abstract: Alzheimer's disease is a modern scourge and is likely to become increasingly so in the future, with increasing longevity. The disease has been investigated for over one hundred years yet its causes and that of the neuropathological characteristics seen in AD brain are still completely unknown. Evidence for a major causative role of a common virus, herpes simplex virus type 1 (HSV1), acting in combination with a genetic factor - the type 4 allele of the apolipoprotein gene, a known susceptibility factor - is presented here. The characteristics of the virus, some of which make it an especially likely candidate for this role, are described, as are the many precedents for the action of a genetic factor modulating outcome of infection. Various possible ways in which HSV1 might lead to development of AD, such as its up-regulation of various enzymes and in particular certain kinases, its effect on the cell cycle, on autophagy, and its inflammatory and oxidative effects are also discussed. It is concluded that there is strong evidence that the virus is indeed a major factor in AD and therefore there is a strong case for appropriate treatment, and possibly for prevention in the future.

Itzhaki RF, Wozniak MA. · Faculty of Life Sciences, The University of Manchester, Moffat Building, PO Box 88, Sackville Street, Manchester M60 1QD, UK. · Prog Lipid Res. · Pubmed #16406033 No free full text.

Abstract: Almost a hundred years ago, the main neuropathological features of Alzheimer's disease (AD) brain were discovered, yet the underlying cause(s) are still unknown, and the disease is basically untreatable. Despite the very numerous studies on the neuropathological features, the cause(s) of their production and whether they have an aetiological role in the disease or are merely end-products ("tombstones") are still unknown. Indeed, until fairly recently, the only known risk factors were age, Down's syndrome and head injury. A susceptibility factor, the type 4 allele of the apolipoprotein E gene was identified, but it is neither essential nor sufficient to cause AD, so other factors must be involved also. We investigated the possibility of a viral role and discovered that HSV1 DNA is present in brain of a high proportion of elderly people and that in combination with APOE-epsilon4 it confers a high risk of AD. Subsequently, we found that APOE determines outcome of infection in several diseases caused by diverse infectious agents. Here we describe our studies, and the few others carried out elsewhere, on the mechanism of action of HSV1 and the dependence of the damage on APOE. We discuss, in relation to HSV1 action on lipids and to the spread of the virus via lipid rafts in brain, the possible involvement in AD of cholesterol, a vital and major component of the human brain, and the dispute over whether statins, drugs used for lowering cholesterol levels, are protective against the disease. We also link the damage due to two major consequences of HSV1 infection--inflammatory and oxidative processes--to lipid peroxidation in brain, and consider the influence of the different apoE isoforms in this process.

Itzhaki RF, Wozniak MA. · Molecular Neurobiology Laboratory, Department of Optomery and Neuroscience, UMIST, PO Box 88, Manchester M60 1QD, United Kingdom. · J Neuroimmunol. · Pubmed #15526402 No free full text.

This publication has no abstract.

Itzhaki RF, Dobson CB, Shipley SJ, Wozniak MA. · Molecular Neurobiology Laboratory, Department of Optometry and Neuroscience, University of Manchester Institute of Science and Technology, P.O. Box 88, Manchester M60 1QD, UK. · Ann N Y Acad Sci. · Pubmed #15246985 No free full text.

Abstract: The virus, herpes simplex virus type 1 (HSV1), when present in brain, acts together with the type 4 allele of the APOE gene, a known susceptibility factor in Alzheimer disease (AD), to confer a strong risk of AD; in carriers of the other two main alleles of the gene, the virus does not confer a risk. It also has been shown that the outcome of infection in the case of five diseases known to be caused by viruses is determined by APOE. It is hoped that the discovery of the involvement of HSV1 in AD will lead to future antiviral therapy and possibly to immunization against the virus in infancy.

Itzhaki RF, Wozniak MA, Appelt DM, Balin BJ. · Department of Optometry and Neuroscience, University of Manchester Institute of Science and Technology (UMIST), Manchester M60 1QD, UK. · Neurobiol Aging. · Pubmed #15172740 No free full text.

Abstract: Despite very numerous studies on Alzheimer's disease (AD), especially on amyloid plaques and neurofibrillary tangles, little information has been obtained thus on the causes of the disease. Evidence is described here that implicates firstly herpes simplex virus type 1 (HSV1) as a strong risk factor when it is present in brain of carriers of the type 4 allele of the gene for apolipoprotein E (APOE-4). Indirect support comes from studies indicating the role of APOE in several diverse diseases of known pathogen cause. A second putative risk factor is the bacterium, Chlamydia pneumoniae. This pathogen has been identified and localized in AD brain. Current studies aimed at "proof of principle" address the entry of the organism into the CNS, the neuroinflammatory response to the organism, and the role that the organism plays in triggering AD pathology. An infection-based animal model demonstrates that following intranasal inoculation of BALB/c mice with C. pneumoniae, amyloid plaques/deposits consistent with those observed in the AD brain develop, thus implicating this infection in the etiology of AD.

Itzhaki RF, Wozniak MA, Dobson CB. · Molecular Neurobiology Laboratory, Department of Optometry and Neuroscience, University of Manchester Institute of Science and Technology, Manchester M60 1QD, UK. · Neurobiol Aging. · Pubmed #12392772 No free full text.

This publication has no abstract.

Wozniak MA, Mee AP, Itzhaki RF. · Faculty of Life Sciences, University of Manchester, UK. · J Pathol. · Pubmed #18973185 No free full text.

Abstract: The brains of Alzheimer's disease sufferers are characterized by amyloid plaques and neurofibrillary tangles. However, the cause(s) of these features and those of the disease are unknown, in sporadic cases. We previously showed that herpes simplex virus type 1 is a strong risk factor for Alzheimer's disease when in the brains of possessors of the type 4 allele of the apolipoprotein E gene (APOE-epsilon4), and that beta-amyloid, the main component of plaques, accumulates in herpes simplex virus type 1-infected cell cultures and mouse brain. The present study aimed to elucidate the relationship of the virus to plaques by determining their proximity in human brain sections. We used in situ polymerase chain reaction to detect herpes simplex virus type 1 DNA, and immunohistochemistry or thioflavin S staining to detect amyloid plaques. We discovered a striking localization of herpes simplex virus type 1 DNA within plaques: in Alzheimer's disease brains, 90% of the plaques contained the viral DNA and 72% of the DNA was associated with plaques; in aged normal brains, which contain amyloid plaques at a lower frequency, 80% of plaques contained herpes simplex virus type 1 DNA but only 24% of the viral DNA was plaque-associated (p < 0.001). We suggest that this is because in aged normal individuals, there is a lesser production and/or greater removal of beta-amyloid (Abeta), so that less of the viral DNA is seen to be associated with Abeta in the brain. Our present data, together with our finding of Abeta accumulation in herpes simplex virus type 1-infected cells and mouse brain, suggest that this virus is a major cause of amyloid plaques and hence probably a significant aetiological factor in Alzheimer's disease. They point to the usage of antiviral agents to treat the disease and possibly of vaccination to prevent it.

Itzhaki RF, Wozniak MA. · Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom. · Rejuvenation Res. · Pubmed #18328007 No free full text.

This publication has no abstract.

Itzhaki RF, Cosby SL, Wozniak MA. · Faculty of Life Sciences, The University of Manchester, Manchester, UK. · J Neurovirol. · Pubmed #18300070 No free full text.

Abstract: The causes of Alzheimer's disease (AD) and of the characteristic pathological features - amyloid plaques and neurofibrillary tangles - of AD brain are unknown, despite the enormous resources provided over the years for their investigation. Indeed, the only generally accepted risk factors are age, Down syndrome, carriage of the type 4 allele of the apolipoprotein E gene (APOE-epsilon 4), and possibly brain injury. Following the authors' previous studies implicating herpes simplex virus type 1 (HSV1) in brain of APOE-epsilon 4 carriers as a major cause of AD, the authors propose here, on the basis of their and others' recent studies, that not only does HSV1 generate the main components of amyloid plaques and neurofibrillary tangles (NFTs) - beta-amyloid (A beta) and abnormally phosphorylated tau but also, by disrupting autophagy, it prevents degradation of these aberrant proteins, leading to their accumulation and deposition, and eventually to AD.

Wozniak MA, Itzhaki RF, Shipley SJ, Dobson CB. · Faculty of Life Sciences, The University of Manchester, PO Box 88, Sackville Street, Manchester M60 1QD, UK. · Neurosci Lett. · Pubmed #17980964 No free full text.

Abstract: It is uncertain whether environmental factors contribute to the formation of senile plaques and neurofibrillary tangles, the abnormal features that define the Alzheimer's disease (AD) brain. We previously proposed that herpes simplex virus type 1 (HSV1) is a strong risk factor for AD when it is present in the brains of people who possess the type 4 allele of the apolipoprotein E gene (APOE-epsilon4); however a direct biochemical link between viral infection and the development of the AD pathological features has never previously been examined. Here we show that infection of cultured neuronal and glial cells with HSV1 leads to a dramatic increase in the intracellular levels of beta-amyloid (Abeta) 1-40 and 1-42, whilst levels of amyloid precursor protein (APP) in cells decrease. Similarly, Abeta1-42 deposits are present in mouse brain after HSV1 infection. In the cultured cells the mechanism involves increased Abeta production, rather than merely greater retention of cellular Abeta, as levels of beta-site APP-cleaving enzyme (BACE-1) and of nicastrin, a component of gamma-secretase, both increase in HSV1-infected cells. These novel data show that HSV1 can directly contribute to the development of senile plaques.

Wozniak MA, Shipley SJ, Combrinck M, Wilcock GK, Itzhaki RF. · Molecular Neurobiology Laboratory, Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom. · J Med Virol. · Pubmed #15602731 No free full text.

Abstract: It was previously shown that herpes simplex virus type 1 (HSV1) DNA resides latently in a high proportion of aged brains and that in carriers of the type 4 allele of the apolipoprotein E gene (APOE-epsilon4), it confers a strong risk of Alzheimer's disease. It was suggested that initial entry of brain by HSV1 and any subsequent reactivation(s) would cause a type of limited encephalitis, the resulting damage being more harmful in APOE-epsilon4 carriers. Reactivation(s) would induce synthesis of intrathecal antibodies; these are long-lived after herpes simplex encephalitis so they were sought in cerebrospinal fluid (CSF) of Alzheimer's disease patients and age-matched normal subjects. Intrathecal antibodies to human herpesvirus 6 (HHV6) were also sought as DNA of this virus has been detected previously in a high proportion of Alzheimer's disease brains. Antibody indices for HSV and HHV6 were measured using indirect ELISA for IgG antibody, and single radial immunodiffusion was used for albumin, in serum and CSF. A raised antibody index (>1.5) indicative of virus-specific intrathecal HSV1 IgG synthesis was found in 14/27 (52%) Alzheimer's disease patients and 9/13 (69%) age-matched normals (difference non-significant). A raised antibody index to HHV6 was detected in 22% of the Alzheimer's disease patients and in no normals, so presumably this virus either did not reactivate in brain or it elicited only short-lived intrathecal antibodies. The HSV1 results confirm the original PCR findings that show the presence of HSV1 DNA sequences in many elderly brains, and indicate also that the whole functional HSV1 genome is present, and that the virus has replicated.

Wozniak MA, Cookson A, Wilcock GK, Itzhaki RF. · Department of Optometry and Neuroscience, Molecular Neurobiology Laboratory, University of Manchester Institute of Science & Technology, Manchester M60 1QD, UK. · Neurobiol Aging. · Pubmed #12927758 No free full text.

Abstract: We recently detected cytomegalovirus (CMV) in brains of 83% of vascular dementia (VaD) patients and 34% of age-matched normal people. Since CMV and also Chlamydia pneumoniae (Cpn) have been found in some studies to be associated with coronary artery disease (which shares several risk factors with VaD), we sought Cpn DNA in VaD brain DNA. We examined brain specimens from 19 VaD patients, 16 elderly normal people and four Alzheimer's disease (AD) patients for the presence of a sequence in the Cpn gene for rRNA, using polymerase chain reaction (PCR) and taking stringent precautions against contamination. We did not detect Cpn DNA in any of the brain specimens, the sensitivity of detection being 10 copies or fewer bacterial DNA sequences per tube or, in terms of infectious units (IFU), 0.025 IFU. Our results do not support a role for Cpn in the aetiology of VaD, either in the 83% of patients in whose brains we detected CMV, or in the remaining 17% without CMV in brain.

Dobson CB, Wozniak MA, Itzhaki RF. · Molecular Neurobiology Laboratory, Department of Optometry and Neuroscience, UMIST, Manchester M60 1QD, UK. · Trends Microbiol. · Pubmed #12875814 No free full text.

This publication has no abstract.

Lin WR, Wozniak MA, Cooper RJ, Wilcock GK, Itzhaki RF. · Department of Optometry and Neuroscience, UMIST, Manchester, UK. · J Pathol. · Pubmed #12115887 No free full text.

Abstract: It has been established, using polymerase chain reaction (PCR), that herpes simplex virus type 1 (HSV1) is present in a high proportion of brains of elderly normal subjects and Alzheimer's disease (AD) patients. It was subsequently discovered that the virus confers a strong risk of AD when in brain of carriers of the type 4 allele of the apolipoprotein E gene (apoE-epsilon4). This study has now sought, using PCR, the presence of three other herpesviruses in brain: human herpesvirus 6 (HHV6)-types A and B, herpes simplex virus type 2 (HSV2) and cytomegalovirus (CMV). HHV6 is present in a much higher proportion of the AD than of age-matched normal brains (70% vs. 40%, p=0.003) and there is extensive overlap with the presence of HSV1 in AD brains, but HHV6, unlike HSV1, is not directly associated in AD with apoE-epsilon4. In 59% of the AD patients' brains harbouring HHV6, type B is present while 38% harbour both type A and type B, and 3% type A. HSV2 is present at relatively low frequency in brains of both AD patients and normals (13% and 20%), and CMV at rather higher frequencies in the two groups (36% and 35%); in neither case is the difference between the groups statistically significant. It is suggested that the striking difference in the proportion of elderly brains harbouring HSV1 and HSV2 might reflect the lower proportion of people infected with the latter, or the difference in susceptibility of the frontotemporal regions to the two viruses. In the case of HHV6, it is not possible to exclude its presence as an opportunist, but alternatively, it might enhance the damage caused by HSV1 and apoE-epsilon4 in AD; in some viral diseases it is associated with characteristic brain lesions and it also augments the damage caused by certain viruses in cell culture and in animals.

Lin WR, Jennings R, Smith TL, Wozniak MA, Itzhaki RF. · University of Manchester Institute of Science & Technology, Molecular Neurobiology Laboratory, Department of Optometry & Neuroscience, M60 1QD, Manchester, UK. · Neurobiol Aging. · Pubmed #11705626 No free full text.

Abstract: Herpes simplex encephalitis (HSE) is a rare but very serious disorder caused by herpes simplex type 1 virus (HSV-1). Treatment with acyclovir decreases mortality but many patients still suffer cognitive impairment subsequently. A vaccine against HSV1 would therefore be of great value. HSV-1 has been implicated also in Alzheimer's disease (AD): we established that HSV1 resides in the brain of about two thirds of AD patients and aged normal people, and that in carriers of the type 4 allele of the apolipoprotein E gene, it is a strong risk factor for AD. Thus a vaccine against HSV-1 might prevent development of AD in some cases. To find whether a vaccine of mixed HSV-1 glycoproteins (ISCOMs), which protects mice from latent HSV-1 infection of sensory ganglia, prevents HSV1 latency in the CNS, ISCOM-vaccinated or unvaccinated animals were infected with HSV-1. Using polymerase chain reaction (PCR) we detected HSV-1 in brain from 16 of 39 unvaccinated mice (41%), but only 3 of 41 vaccinated mice (7%) (P < 0.001). Thus, ISCOMs protect the CNS also, suggesting their possible future usage in humans.

Lin WR, Wozniak MA, Esiri MM, Klenerman P, Itzhaki RF. · Molecular Neurobiology Laboratory, Department of Optometry and Neuroscience, UMIST, Manchester M60 1QD, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #11118260 links to  free full text

Abstract: It was previously found that herpes simplex type 1 virus (HSV1) when present in the brain, is a risk factor for Alzheimer's disease in carriers of the type 4 allele of the gene for apolipoprotein E (apoE epsilon4), and apoE epsilon4 is a risk factor for herpes labialis. Whether a specific allele of the gene is involved in susceptibility to another disorder caused by HSV1-herpes simplex encephalitis (HSE)-has now been investigated. DNA was prepared from formalin-fixed, paraffin-embedded blocks of specimens from the brain or spleen of 14 United Kingdom patients with HSE, confirmed by necropsy, and from the CSF of seven United Kingdom clinical patients with HSV1 in their CSF detected by polymerase chain reaction (PCR). ApoE genotype of the DNA from blocks was determined by seminested PCR, and of the DNA from CSF by one step PCR, followed by restriction endonuclease digestion. The apoE allele frequencies were compared with values previously obtained for 238 normal people from the United Kingdom. The apoE epsilon2 allele frequency of the patients with HSE was 26%, significantly higher than the value of 7% for the normal subjects (OR=4.6, 95% confidence interval (95% CI) 2. 0-10.8). The apoE epsilon3 and epsilon4 allele frequencies did not differ significantly between the two groups. Thus, it seems that apoE epsilon2 is a risk factor for HSE.

Itzhaki RF, Wozniak MA. · No affiliation provided · J Am Geriatr Soc. · Pubmed #17233703 No free full text.

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Itzhaki RF, Dobson CB, Wozniak MA. · No affiliation provided · Aging Cell. · Pubmed #15038823 No free full text.

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Itzhaki RF, Dobson CB, Wozniak MA. · No affiliation provided · Ann Neurol. · Pubmed #14755740 No free full text.

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Itzhaki RF, Dobson CB, Lin WR, Wozniak MA. · No affiliation provided · J Neurovirol. · Pubmed #11704890 No free full text.

This publication has no abstract.