We are glad that the data of Letenneur et al. are broadly consistent with our work indicating that herpes simplex virus type 1 (HSV1) has a role in Alzheimer’s disease (AD). However there are a few details missing in the paper, such as the fact that we have shown that HSV1 increases the amount of β-amyloid (Aβ) in infected cell cultures and in infected mouse brains [1]. In that study we used several anti-Aβ antibodies, including one that recognises the N-terminal end of Aβ, i.e., an antibody that binds to the part of Aβ that is not homologous to the viral glycoprotein B protein. More recently, we have revealed that HSV1 DNA localises very specifically in amyloid plaques in AD brains [2]. These data together suggest that in AD, the virus causes Aβ accumulation and formation of amyloid plaques. Further, we have data in press showing that HSV1 infection of cultured cells causes another AD-like feature – abnormal phosphorylation of tau [3].
As to our “controversial” findings on APOE-ε4 and HSV1 presence in brain of AD patients, in fact our data were subsequently supported by Itabashi et al. [4], while the results of Beffert et al. [5], which are cited as disagreeing with ours, show a trend toward an HSV1-APOE-ε4 association although it did not reach statistical significance [6,7]. Our other studies on APOE support our concept of HSV1-APOE-ε4 action in AD in revealing that APOE-ε4 is a risk factor for herpes labialis (cold sores) [8,9], which is definitely caused by HSV1 in the peripheral nervous system (PNS), and that APOE determines outcome of infection in the case of several diverse microbes [10-14].
Our studies seeking IgG in the cerebrospinal fluid (CSF) showed that antibodies to HSV are detectable in a high proportion of AD patients and age-matched normals, indicating that the virus reactivates in brain, perhaps recurrently. We have suggested that reactivation of latent HSV1 in brain occurs on stress, immunosuppression, etc, as in the PNS, and occurs also on systemic infection [15], as a consequence of the inflammation it is thought to cause in the brain [16]. Reactivation would then lead to direct viral damage and to indirect inflammatory damage. The results of Letteneur et al. on IgM in serum reflect HSV reactivation events in the PNS, and it seems likely that stress and the other stimulatory factors cause reactivation concurrently in the PNS and the brain, with harmful consequences in APOE-ε4 carriers. Thus, monitoring serum for IgM might provide a means of monitoring such events in the brain, at least in some patients.

Ruth F. Itzhaki and Matthew A. Wozniak
University of Manchester

References

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