Matthew A. Wozniak

Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques.

The brains of Alzheimers 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 Alzheimers disease when in the brains of possessors of the type 4 allele of the apolipoprotein E gene (APOE‐ε4), and that β‐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 Alzheimers 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 β‐amyloid (Aβ), so that less of the viral DNA is seen to be associated with Aβ in the brain. Our present data, together with our finding of Aβ 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 Alzheimers disease. They point to the usage of antiviral agents to treat the disease and possibly of vaccination to prevent it. Copyright

Herpes simplex virus infection causes cellular β-amyloid accumulation and secretase upregulation

It is uncertain whether environmental factors contribute to the formation of senile plaques and neurofibrillary tangles, the abnormal features that define the Alzheimers 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.

Alzheimer's disease and infection: Do infectious agents contribute to progression of Alzheimer's disease?

Infection with several important pathogens could constitute risk factors for cognitive impairment, dementia, and Alzheimers disease (AD) in particular. This review summarizes the data related to infectious agents that appear to have a relationship with AD. Infections with herpes simplex virus type 1, picornavirus, Borna disease virus, Chlamydia pneumoniae, Helicobacter pylori, and spirochete were reported to contribute to the pathophysiology of AD or to cognitive changes. Based on these reports, it may be hypothesized that central nervous system or systemic infections may contribute to the pathogenesis or pathophysiology of AD, and chronic infection with several pathogens should be considered a risk factor for sporadic AD. If this hypothesis holds true, early intervention against infection may delay or even prevent the future development of AD.

Herpes simplex virus type 1 in Alzheimer's disease: the enemy within.

Alzheimers 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.

Alzheimer's disease-specific tau phosphorylation is induced by herpes simplex virus type 1.

Neurofibrillary tangles are one of the main neuropathological features of Alzheimers disease (AD) and are composed of abnormally phosphorylated forms of a microtubule-associated protein called tau. What causes this abnormal phosphorylation is unknown. Our previous studies have implicated herpes simplex virus type 1 (HSV1) as an etiological agent in AD, and so we investigated whether infection with this virus induces AD-like tau phosphorylation. Here we demonstrate that HSV1 causes tau phosphorylation at several sites, including serine 202, threonine 212, serine 214, serine 396 and serine 404. In addition, we have elucidated the mechanism involved by showing that the virus induces glycogen synthase kinase 3beta and protein kinase A, the enzymes that cause phosphorylation at these sites. Our data clearly reveal the importance of HSV1 in AD-type tau phosphorylation, and support the case that the virus is a cause of the disease. Together with our previous data, our results point to the use of antiviral agents to slow the progression of the disease.

Antivirals Reduce the Formation of Key Alzheimer's Disease Molecules in Cell Cultures Acutely Infected with Herpes Simplex Virus Type 1

Alzheimers disease (AD) afflicts around 20 million people worldwide and so there is an urgent need for effective treatment. Our research showing that herpes simplex virus type 1 (HSV1) is a risk factor for AD for the brains of people who possess a specific genetic factor and that the virus causes accumulation of key AD proteins (β-amyloid (Aβ) and abnormally phosphorylated tau (P-tau)), suggests that anti-HSV1 antiviral agents might slow AD progression. However, currently available antiviral agents target HSV1 DNA replication and so might be successful in AD only if Aβ and P-tau accumulation depend on viral DNA replication. Therefore, we investigated firstly the stage(s) of the virus replication cycle required for Aβ and P-tau accumulation, and secondly whether antiviral agents prevent these changes using recombinant strains of HSV1 that progress only partly through the replication cycle and antiviral agents that inhibit HSV1 DNA replication. By quantitative immunocytochemistry we demonstrated that entry, fusion and uncoating of HSV1, are insufficient to induce Aβ and P-tau production. We showed also that none of the “immediate early” viral proteins is directly responsible, and that Aβ and P-tau are produced at a subsequent stage of the HSV1 replication cycle. Importantly, the anti-HSV1 antiviral agents acyclovir, penciclovir and foscarnet reduced Aβ and P-tau accumulation, as well as HSV1, with foscarnet being less effective in each case. P-tau accumulation was found to depend on HSV1 DNA replication, whereas Aβ accumulation was not. The antiviral-induced decrease in Aβ is attributable to the reduced number of new viruses, and hence the reduction in viral spread. Since antiviral agents reduce greatly Aβ and P-tau accumulation in HSV1-infected cells, they would be suitable for treating AD with great advantage unlike current AD therapies, only the virus, not the host cell, would be targeted.

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 Alzheimers 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.

Do infectious agents play a role in dementia

Abstract The number of people surviving to old age and concomitantly, the number affected by the diseases of old age, is increasing steadily. Alzheimers disease (AD) affects one in five people aged over 80. The causes are unknown, but obviously, elucidation of the mechanisms of initiation and development of the disease is urgently required. This review describes studies on the possible role of infectious agents in dementia, particularly those on herpes simplex virus type 1, which, we discovered, resides latently in a high proportion of brains of the elderly and in combination with a certain genetic factor, is responsible for a high proportion of AD cases.

Antiviral agents in Alzheimer’s disease: hope for the future?

Alzheimer’s disease (AD) is characterized by loss of memory and intellectual function. It currently afflicts around 18 million people worldwide but the total numbers affected, if carers and relatives are included, are far greater. AD places enormous emotional and financial burdens on individuals and the state, and as more people are predicted to survive to old age, these burdens will increase if no effective treatment is discovered. AD is categorized by age of onset (early versus late onset) and by whether there is an inherited component to the disease (familial versus sporadic). Except for a small number of early-onset, familial AD cases that have a clear genetic component, the causes of AD are unclear, although risk factors for the disease are known and include increasing age, Downs syndrome, and possibly head injury. Accumulating evidence suggests that infectious agents are important etiological factors in AD. Superficially, infectious agents such as viruses and bacteria might not seem likely candidates as causes of chronic diseases. This is perhaps because microbes are generally known to be the cause of many acute illnesses, and so they are assumed to vanish or to be expunged from the body when the illness ends. However, this reasoning fails to take into account the ability of many micro-organisms to remain in a dormant state until certain events reawaken them to a virulent state. This process of dormancy followed by activation makes infectious agents prime candidates as factors in chronic diseases. Certainly, there are a number of major precedents for the correctness of such a ‘heretical’ concept, for example, viruses in various cancers, and the bacterium Helicobacter pylori in stomach ulcers [Marshall and Warren, 1984]. In the case of AD, several agents have been proposed but the focus of this review is the evidence for an involvement of herpes simplex virus type 1 (HSV1). The rationale for implicating HSV1, a neurotropic virus, in AD is based on several facts. First, initial infection with this virus usually occurs in infancy and once infected it remains lifelong in the peripheral nervous system (PNS) in a latent state. However, HSV1 can be reactivated repeatedly by events such as stress and immunosuppression, leading to a productive infection and virus replication, and in some people this results in herpes labialis (cold sores). Thus, if HSV1 were eventually to reach the brain, repeated reactivation of the virus there could lead to accumulation of damage, manifesting at a late stage in life, consistent with the onset of AD usually in older age. Second, the virus is ubiquitous, infecting about 90% of the adult population: a necessary characteristic in view of the high prevalence of AD. Finally, HSV1 causes a rare but severe brain disorder, herpes simplex encephalitis (HSE), and the main regions affected, the frontal and temporal cortices, are those showing the main pathological changes in AD; for these reasons, the virus was proposed as a likely candidate agent in AD [Ball, 1982]. Further, those who survive HSE usually suffer from memory loss and cognitive impairment [Hokkanen and Launes, 2000]. This review focuses on the questions that have been asked in order to investigate a possible role for HSV1 in AD (but omits descriptions of the virus lifecycle and of certain viral effects that may play a role, such as oxidation and autophagy, as they were discussed in a previous review [Itzhaki and Wozniak, 2008]). Further, it describes the use of current and of possible future antiviral agents.

Herpes simplex virus type 1 and Alzheimer’s disease: The autophagy connection

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-ε4), and possibly brain injury. Following the authors’ previous studies implicating herpes simplex virus type 1 (HSV1) in brain of APOE-ε4 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)—β-amyloid (Aβ) 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.