P4-029: Herpes simplex virus type 1 (HSV1) in brain: A cause of the neuropathological features of Alzheimer's disease?

Abstract

The causes of AD remain unknown, despite extensive studies on amyloid plaques and neurofibrillary tangles. We have implicated the virus, HSV1, as a major factor. We discovered that latent HSV1 is present in a high proportion of elderly brains (Jamieson et al., 1991), and in carriers of the type 4 allele of the apolipoprotein E gene (APOE-e4) it confers a strong risk of AD (Itzhaki et al., 1997); also, it reactivates from latency in brain, causing an acute infection – possibly recurrently (Wozniak et al., 2005). Immunocytochemistry; ELISA; Western blotting; in situ PCR. We have linked HSV1 directly to AD brain abnormalities: (1) HSV1 infection of cultured cells causes intracellular deposition of Aβ (Wozniak et al., 2007); (2) HSV1 infection of mice results in Aβ deposition in brain (Wozniak et al., 2007); (3) HSV1 infection of cultured cells causes AD-like phosphorylation of tau (Wozniak et al., to be submitted). These changes result from increases in the relevant secretases and kinases, and are likely due to HSV1 subverting cell processes to aid its replication, taking over the protein-synthesising machinery, and causing entry into cycle, although as in AD, only up to G2/M. As for the role of APOE-e4 with HSV1 in AD, we propose that it determines extent of HSV1 damage. This is strongly supported by our discovery that APOE determines outcome of infection in several diseases of known microbial cause (Wozniak & Itzhaki, 2006). Further, on examining HSV1 location in relation to amyloid plaques in AD brain, we found 90% of plaques associated with viral DNA and most of the viral DNA is located in plaques (Wozniak et al., submitted). This co-localisation, together with our discovery that HSV1 induces amyloid deposition, strongly implicates HSV1 in plaque formation and AD development (we can refute explanations that co-localisation results from plaque formation). Our data strongly implicate HSV1 as a major factor in AD. They support antiviral usage to prevent deterioration of patients and possibly in future, vaccination against HSV1 (which protects against establishment of viral latency in mouse brain – Lin et al., 2001) to prevent AD occurrence.