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Biomedical subjects

Ruth F Itzhaki

Publications and source records attributed to Ruth F Itzhaki.

16 recordsLinked to original sources
PubMed2005

Herpes simplex virus type 1, apolipoprotein E, and cholesterol: a dangerous liaison in Alzheimer's disease and other disorders.

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.

Aged↗
PubMed2005

Herpes simplex virus interferes with amyloid precursor protein processing.

BACKGROUND: The early events underlying Alzheimer's disease (AD) remain uncertain, although environmental factors may be involved. Work in this laboratory has shown that the combination of herpes simplex virus type 1 (HSV1) in brain and carriage of the APOE-epsilon4 allele of the APOE gene strongly increases the risk of developing AD. The development of AD is thought to involve abnormal aggregation or deposition of a 39-43 amino acid protein--beta amyloid (Abeta)--within the brain. This is cleaved from the much larger transmembranal protein 'amyloid precursor protein' (APP). Any agent able to interfere directly with Abeta or APP metabolism may therefore have the capacity to contribute towards AD. One recent report showed that certain HSV1 glycoprotein peptides may aggregate like Abeta; a second study described a role for APP in transport of virus in squid axons. However to date the effects of acute herpesvirus infection on metabolism of APP in human neuronal-type cells have not been investigated. In order to find if HSV1 directly affects APP and its degradation, we have examined this protein from human neuroblastoma cells (normal and transfected with APP 695) infected with the virus, using Western blotting. RESULTS: We have found that acute HSV1 (and also HSV2) infection rapidly reduces full length APP levels--as might be expected--yet surprisingly markedly increases levels of a novel C-terminal fragment of APP of about 55 kDa. This band was not increased in cells treated with the protein synthesis inhibitor cycloheximide CONCLUSION: Herpes virus infection leads to rapid loss of full length APP from cells, yet also causes increased levels of a novel 55 kDa C-terminal APP fragment. These data suggest that infection can directly alter the processing of a transmembranal protein intimately linked to the aetiology of AD.

Alzheimer Disease↗
PubMed2005

Productive herpes simplex virus in brain of elderly normal subjects and Alzheimer's disease patients.

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.

Adolescent↗
PubMed2003

Absence of Chlamydia pneumoniae in brain of vascular dementia patients.

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.

Aged↗
PubMed2002

Herpesviruses in brain and Alzheimer's disease.

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.

Aged↗
PubMed2002

Cytomegalovirus is present in a very high proportion of brains from vascular dementia patients.

We previously found that herpes simplex type 1 virus (HSV1), when present in brain of carriers of the apolipoprotein E type 4 allele is a strong risk factor for Alzheimer's disease. To find if HSV1 or certain other herpesviruses are involved in vascular dementia (VaD), we searched post mortem brain specimens from patients suffering from VaD for the presence of HSV1, cytomegalovirus (CMV), and human herpesvirus type 6 DNA, using polymerase chain reaction. We have found that a very high proportion of the VaD patients, 93% (14/15), but not of age-matched normals, 34% (10/29), harbor CMV DNA (P = 0.0002); the proportions of the patients harboring the other viruses in brain do not differ significantly from those of the normals. Further studies are needed to reveal whether or not the association of CMV with VaD is causal.

Aged↗
PubMed2002

Apolipoprotein E-epsilon 4 protects against severe liver disease caused by hepatitis C virus.

The outcome of infection with hepatitis C virus (HCV) varies greatly. The virus associates with serum lipoproteins, including those containing apolipoprotein E (apoE) and apolipoprotein B (apoB), and may enter cells via the low-density lipoprotein receptor (LDLR). ApoE genotypes can affect the extent of damage in diseases caused by 2 other viruses--herpes simplex virus type 1 (HSV1; in Alzheimer's disease and herpes labialis) and human immunodeficiency virus (HIV). We therefore investigated whether specific apoE and apoB alleles were associated with different outcomes of HCV infection. A total of 156 anti-HCV-positive patients and 104 non-HCV-infected patients were studied. Liver biopsy specimens from patients with chronic HCV infection (n = 111) were assessed for disease severity by the Knodell system. ApoE and apoB genotypes were determined by standard polymerase chain reaction (PCR) methods. There was no significant difference among the apoE genotypes of HCV-infected subjects compared with previously published population data, or between HCV-RNA positive or negative patients. However, chronically HCV-infected subjects with mild liver disease (n = 65) had a significantly higher apoE-epsilon 4 allele frequency (20.0%) than those (n = 46) with severe disease (6.5%). ApoB alleles alone or in combination with apoE were not associated with mild or severe disease. The overall apoE allele frequencies of patients with liver disease not caused by HCV were similar to those of the total HCV group and in contrast to the HCV patients, the apoE allele frequencies were similar in those patients with no or mild fibrosis as compared with those with bridging fibrosis or cirrhosis. In conclusion, carriage of an apoE-epsilon 4 allele may be protective against liver damage caused by HCV, but not against damage due to various nonviral causes. This is yet another case in which apoE may determine the severity of a viral disease.

Adult↗
PubMed2002

The significance of environmental factors in the etiology of Alzheimer's disease.

The proposition that environmental agents, such as diet, aluminum, and viruses, are as important as genetic factors in the etiology of Alzheimer's disease (AD) was advanced by the authors at the Challenging Views of Alzheimer's Disease meeting held in Cincinnati on July 28 and 29, 2001. Diet, dietary fat, and to a lesser extent, total energy (caloric intake), were found to be significant risk factors for the development of AD in a dozen countries, while fish consumption was found to be a significant risk reduction factor. An acid-forming diet, such as one high in dietary fat or total energy, can lead to increased serum and brain concentrations of aluminum and transition metal ions, which are implicated in oxidative stress potentially leading to the neurological damage characteristic of AD. Many of the risk factors for AD, such as cholesterol and fat, and risk reduction factors, such as whole grain cereals and vegetables, are shared with ischemic heart disease. Aluminum may cause neurological damage and a number of studies have linked aluminum to an increased risk for developing AD. The evidence for viral agents playing a role in AD is the strong association between the presence of HSV1 in brain and carriage of an apoE-epsilon4 allele in the case of AD patients but not of controls; statistical analysis shows the association is causal. Diet, aluminum, and viral infections may increase the prevalence of AD by eliciting inflammation, which may cause the neurological damage that results in AD.

Aged↗