Cell and Molecular Biology of Alzheimer's Disease and Neurovirology
Alzheimer’s disease (AD) affects 18 million people worldwide, and the numbers will rise with increasing longevity. Currently, neither prevention nor treatment is available. Indeed, the causes of AD are unknown, as are those of the main abnormal brain features, amyloid plaques and neurofibrillary tangles, which are thought to be involved in disease development. Our results indicate that a virus plays a major role in AD. This points to antiviral treatment to slow deterioration in those afflicted, and vaccination to prevent AD.
Several common viruses can cause serious neurological disease years after initial infection. In AD, herpes simplex virus type 1 (HSV1) was originally suggested as a candidate agent as it is ubiquitous, and in the acute brain infection, herpes simplex encephalitis (HSE), it affects the same brain regions as those most damaged in AD. However, it was uncertain whether HSV1 was present in the brain in normal circumstances. We discovered by using polymerase chain reaction that HSV1 DNA indeed resides in brain of a high proportion of AD patients and elderly normals, and using an immunological technique we substantiated viral presence and showed that it is active there.
HSV1 DNA presence in elderly normal as well as AD patients’ brains does not preclude a viral role in AD. Microbial infection can be asymptomatic, the outcome probably depending on host genetic factors. In fact we found a strong association between HSV1 presence in brain and carriage of the type 4 allele (APOE-e4) of the gene encoding apolipoprotein E, a known susceptibility factor for AD. The combination accounted for 60% of our cases. Also, a high proportion of sufferers from cold sores, which are caused usually by HSV1, were APOE-e4 carriers. We therefore suggested that HSV1 and APOE-e4 together are particularly harmful in the nervous system, and that as in the peripheral nervous system, HSV1 reactivates from latency in brain during stress, immunosuppression, etc, causing localised damage which is greater in APOE-e4 carriers, leading to AD.
HSV1 and the protein, apoE, might compete for cell entry, as both bind to certain surface molecules, and the extent of competition could determine extent of damage. In fact we found that APOE governs outcome of infection by several other microbes that use the surface molecules.
We then discovered direct links between HSV1 and the abnormalities of AD brain: HSV1 infection of cultured cells leads to deposition of β-amyloid (Aβ), the main component of plaques, and infection of mice results in Aβ deposition in brain. Also, in cultured cells, HSV1 causes AD-like phosphorylated tau (P-tau), the main component of tangles. Further, on investigating the location of HSV1 in AD brain, we found, excitingly, that most of the viral DNA is associated with plaques and almost all plaques contain HSV1 DNA. Association does not prove causality, but together with the HSV1-induced increase in Aβ, the data strongly suggest that HSV1 is responsible for production of amyloid and its toxic products and thus for plaque formation in AD brains.
Recently we investigated the effects of an antiviral agent on the HSV1-induced production of Aβ and P-tau. Anti-HSV1 antiviral agents such as acyclovir (ACV) would prevent HSV1-induced damage that depends on viral DNA synthesis, and also other HSV1 damage by decreasing viral spread. We found that ACV greatly reduces Aβ and P-tau, thus substantiating its use for AD treatment, especially as ACV, unlike other AD treatments, would not target normal cell products.