Herpes simplex virus type 1 in brain and apolipoprotein E type 4 allele: a dangerous liaison for Alzheimer's disease.





R.F. Itzhaki, S. J. Shipley, C.B. Dobson, M.A. Wozniak

University of Manchester, Faculty of Life Sciences, North Campus, Moffat Building, Sackville Street, Manchester M60 1QD, UK.



Infectious agents have been proposed as factors in several chronic diseases, especially the age-associated ones, heart disease and Alzheimer's disease (AD). We have implicated herpes simplex virus type 1 (HSV1) in the aetiology of AD. We discovered, using solution PCR, that HSV1 DNA resides latently in brain of a high proportion of elderly people, and that in brain of carriers of the type 4 allele of the apolipoprotein E gene it confers a strong risk of AD (Itzhaki et al., 1997). HSV1-APOE interaction in AD is strongly supported by our finding that APOE determines disease severity in disorders caused by diverse pathogens (see Dobson et al., 2003). Further evidence for HSV1 in brain - and its replication - is afforded by our finding intrathecal antibodies to HSV1 (these are long-lived) in many elderly people (Wozniak et al., 2005). Very recently, we have shown by yet another method - in situ PCR - that HSV1 DNA resides in AD brain, in neurons and glial cells. Also, we have found that HSV1 infection of cultured neural cells increases greatly the amount of beta-amyloid 42 within cells; this peptide is the main component of the characteristic amyloid plaques of AD brain and its formation - whether harmful or protective - may be a major factor in the early stages of AD.
We suggest that stress or peripheral infection causes cytokine entry into brain and the consequent inflammation reactivates latent HSV1; the activated virus augments the inflammation (cf. enhanced inflammation in mice with pre-clinical prion disease - Combrinck et al., 2002), and brain damage perhaps via production of beta-amyloid 42, especially in APOE-e4 carriers - leading eventually to AD. Research by others has shown a link between amyloid precursor protein or amyloid and HSV1, and epidemiological studies suggest that infection and stress cause cognitive decline. Our results implicating HSV1 in brain indicate that AD may be treatable with antiviral agents, and perhaps in future preventable by vaccination against HSV1.




Key words: Alzheimer's disease, herpes simplex virus type 1, apolipoprotein E, amyloid, inflammation







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