Herpes simplex virus type 1 and the type 4 allele of the apolipoprotein E gene in Alzheimer's disease

Infectious agents are putative factors in several chronic diseases, especially the age-associated ones, heart disease and Alzheimer's disease (AD). Our aim is to elucidate the role of herpes simplex virus type 1 (HSV1) in AD, following our discovery that HSV1 resides latently in brain of many elderly people, and that in brain of APOE-e4 carriers, it confers a major risk of AD. HSV1-APOE interaction in AD is strongly supported by our finding that APOE determines disease severity in disorders caused by diverse pathogens. Further evidence for HSV1 presence in brain - and for its having replicated there, perhaps recurrently - is afforded by our detecting intrathecal antibodies to HSV1 (these are long-lived) in many elderly people and, by in situ PCR, detecting HSV1 DNA in neurons and glial cells. We recently discovered that HSV1 infection of cultured neural cells affects the degradation of amyloid precursor protein (APP); also, it causes deposition of intracellular beta-amyloid 42. Further, the level of abnormally phosphorylated tau too increases in the infected cells. Preliminary experiments suggest that in brain of HSV1-infected mice, there is an accumulation of beta-amyloid 42. Results of others, including epidemiological data, indicate that infection and stress cause cognitive decline, probably via cytokine entry into brain and consequent inflammation. We propose that latent HSV1 is reactivated by the inflammation which, in turn, is augnmented by the activated virus (cf. enhanced inflammation in mice with pre-clinical prion disease); damage is thereby increased - perhaps via beta-amyloid 42 production - especially in APOE-e4 carriers, leading eventually to AD. Our amyloid data are the first to point to an actual cause of the abnormal deposition of beta-amyloid in brain of sporadic AD sufferers and, by implicating HSV1, they indicate the usage of antiviral agents for treatment, and perhaps of vaccination against HSV1 for prevention of AD. The latter possibility is supported by our finding that vaccination of mice against HSV1 is highly protective against establishment of viral latency in brain.