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

Abstract

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, Down's 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.