Wozniak MA, Mee AP, Itzhaki RF.
Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques.
J Pathol. 2009 Jan;217(1):131-8.
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Dr. Itzhaki and colleagues provide additional evidence implicating HSV-1 as playing some role in AD. Whether that role is active or passive is still in dispute and the literature bearing on this question is not consistent. However, barring technical issues that might give rise to false positive results, the demonstration of HSV-1 DNA in AD plaques is an important piece of the puzzle. The hypothesis that this virus plays a direct role in AD does not require its ongoing presence in plaques, but the fact that such evidence exists supports the long-standing, but controversial, idea that pathogens may participate in chronic neurodegenerative diseases such as AD (see Paul Ewald’s book, Plague Time, for a general discussion of this topic). In my opinion, this hypothesis deserves more attention than it receives. This is difficult work and this group should be commended for continuing to test this hypothesis in the face of a largely apathetic, if not antagonistic, research community. As the authors note, association is not evidence of causality, but viral presence, if confirmed, certainly warrants further study. An intriguing possibility, suggested a few years ago by Robinson and Bishop (Robinson and Bishop, 2002), is that the amyloid peptide serves as a “bioflocculent” to trap pathogens and/or toxins. If so, there may be other pathogens found in plaques (and some reports of such). But one pathogen should be enough to capture the interest of those seeking to identify the underlying cause of sporadic AD, a question that remains, somewhat surprisingly, unanswered.
Robinson SR, Bishop GM.
Abeta as a bioflocculant: implications for the amyloid hypothesis of Alzheimer's disease.
Neurobiol Aging. 2002 Nov-Dec;23(6):1051-72.
Comment by Hyun-pil Lee, Rudy J. Castellani, George Perry, Akihiko Nunomura, Xiongwei Zhu, Mark A. Smith, Hyoung-gon Lee
HSV, Amyloid, and Alzheimer Disease
Wozniak and colleagues show the localization of herpes simplex virus (HSV) 1 DNA within amyloid plaques both in Alzheimer disease (AD) brains as well as in the brains of aged normal subjects (1). The genetic interaction between the localization of HSV1 DNA in plaques and apolipoprotein E-ε4 allele, a risk factor of AD is interesting and potentially very exciting. This provocative observation suggests that HSV1 may be involved in plaque formation in sporadic AD. However, since HSV1 is present in a high proportion of elderly brains and plaque formation is a common feature of the aging human brain that can occur in the absence of cognitive decline (2-4), the causal relationship between HSV1 and neuronal loss or synaptic loss, which are more reliable predictors of cognitive decline, remains to be delineated. In addition, oxidative stress has been found to precede amyloid deposition in sporadic and familial AD (5-7), and one cannot completely exclude the possibility that the involvement of HSV1, like amyloid (4,8), is a response to disease.
Wozniak MA, Mee AP, Itzhaki RF.
Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques.
J Pathol. 2009 Jan;217(1):131-8.
Castellani RJ, Lee HG, Zhu X, Perry G, Smith MA.
Alzheimer disease pathology as a host response.
J Neuropathol Exp Neurol. 2008 Jun;67(6):523-31.
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The aging brain.
Annu Rev Pathol. 2008;3:41-66.
Smith MA, Casadesus G, Joseph JA, Perry G.
Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brain.
Free Radic Biol Med. 2002 Nov 1;33(9):1194-9.
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA.
Oxidative damage is the earliest event in Alzheimer disease.
J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67.
Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, Smith MA.
RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease.
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Nunomura A, Chiba S, Lippa CF, Cras P, Kalaria RN, Takeda A, Honda K, Smith MA, Perry G.
Neuronal RNA oxidation is a prominent feature of familial Alzheimer's disease.
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Castellani RJ, Lee HG, Zhu X, Nunomura A, Perry G, Smith MA.
Neuropathology of Alzheimer disease: pathognomonic but not pathogenic.
Acta Neuropathol. 2006 Jun;111(6):503-9.
Potentially important and interesting observations which need to be independently replicated.
The issue of whether infectious agents, such as viruses, may be involved in the onset and/or the progression of Alzheimer disease (AD) has been floating around since at least 1980 (1). In particular, there has been much speculation on the possibility that the neurotrophic human herpes virus type 1 (HSV1) may play a role in the pathogenesis of Alzheimer disease (2-6). Interestingly, there is even sequence homology between one of the HSV1 proteins, glycoprotein B, and Aβ, and the homologous region of glycoprotein B rapidly forms amyloid-like fibrils and has significant neurotoxicity in vitro (7). Ruth Itzhaki’s laboratory has, more or less continuously since 1994, been investigating whether HSV1 has a role in the onset and progression of AD (8). The recent manuscript by Wozniak et al., “Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques,” provides some new data on the location of HSV1 DNA in the AD brain and in the brains of non-demented age-matched controls (9).
Wozniak and colleagues report “a striking localization of HSV1 DNA within plaques in AD brains (90 percent) and 72 percent of the DNA was associated with plaques in aged normal brains.” They suggest that “the difference probably relates to a greater production and/or lesser removal of Aβ in APOE-ε4 carriers.” They conclude that “HSV1 is the major cause of amyloid plaques and hence probably a significant etiological factor in AD.” However, this statement is not supported by the currently available data on HSV1 and AD. While the data presented is intriguing, the authors admit association does not prove causation, and APOE-ε4 carriers are already known to have a significantly higher risk of developing AD. Therefore, the putative role of HSV1 in the onset and/or progression of AD remains unknown. Finally, they promote “the usage of antiviral agents to treat the disease and possibly of vaccination to prevent it.” Unfortunately, because of the high incidence of HSV1 infection in both AD patients and non-demented age-matched controls, there is no clear-cut linkage between HSV1 infection and AD. A final point that should be considered is the recent emphasis on soluble/oligomeric forms of the Aβ as the disease-causing forms of the peptide, which was not addressed in the current manuscript. In summary, the manuscript represents an extension on previous publications by Dr. Itzhaki concerning the putative role of HSV1 in AD. Ultimately, the role of HSV1 in AD will need to be addressed by experiments with HSV1-infected APP transgenic mice, or more definitively by clinical trials in humans using either antiviral agents or an antiviral vaccine.
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While genetic susceptibility to familial and sporadic Alzheimer disease has become definitive, for decades the AD field has struggled with possible environmental initiators of, or contributors to AD pathoetiology. Suggestions have been made that heavy metals such as aluminum, copper, zinc, and even iron at high levels might represent AD environmental risk factors. Further, infectious agents such as the bacterium Chlamydia pneumoniae and herpes viruses have also been suggested to precipitate AD pathology. While putative roles of these environmental AD risk factors are controversial, it is nonetheless critically important to determine if such factors are involved in the etiopathogenesis of AD.
In a recent report, Wozniak and colleagues (2009) have investigated a possible infectious organism connection with AD, and find an interesting association between β amyloid plaques and herpes simplex virus type I (HSV-1) DNA. They have compared AD patient brains with brains from “normal” aged brains (that demonstrate a lower frequency of β amyloid plaques without cognitive impairment). Specifically, the authors show that 72 percent of the HSV-1 DNA detected was localized to β amyloid plaques, whereas a meager 24 percent of HSV-1 viral DNA was detected in β amyloid plaques from non-demented elderly individuals. It should be noted that HSV-1 infection becomes latent in the ganglia within a matter of weeks, and is not generally detected in the CNS during the latent stage of infection. This highlights the uniqueness of the current study, as the authors find a specific association between viral DNA and amyloid plaques. The authors conclude that “this virus is a major cause of amyloid plaques and hence probably a significant etiological factor in Alzheimer’s disease.” While this may be the case, it is too early to make this conclusion. The definitive study would be to infect one of the AD mouse models with HSV-1 at an age prior to cerebral β amyloid deposition and determine whether the HSV-1 precipitates the plaques.
Nonetheless, these results raise the interesting possibility that brain infection with viruses might trigger AD-type pathology. Along these lines, it is curious that another brain infectious virus, West Nile virus (which is both neurovirulent and neurotrophic, like HSV-1), is well known to lead to encephalitis, meningitis, and even death in the elderly, whereas healthy adults are typically asymptomatic and clear the virus. We have recently shown that a key part of host immune defense against lethal West Nile encephalitis is Toll-like receptor 7, which triggers an interleukin-23-dependent leukocyte homing and infiltration response into the brain, resulting in viral neutralization and clearance (Town et al., 2009). We also have evidence that Toll-like receptor signaling is hypoactive in elderly vs. young adults. It will be interesting to determine the molecular mechanisms for how these brain infectious viruses lead to susceptibility to disease in the elderly, including brain inflammation (encephalitis) and perhaps AD.
Town T, Bai F, Wang T, Kaplan AT, Qian F, Montgomery RR, Anderson JF, Flavell RA, Fikrig E.
Toll-like receptor 7 mitigates lethal West Nile encephalitis via interleukin 23-dependent immune cell infiltration and homing.
Immunity. 2009 Feb 20;30(2):242-53.
We thank the commentators for their (mostly) positive views and hope that our results will stimulate further interest rather than the apathy or hostility that Keith Crutcher justifiably mentions. There are five points we'd like to raise:
1. The essence of the paper is that almost all plaques contain viral DNA (90 percent and 80 percent, respectively, for ADs and normals) and more importantly, a high proportion of the viral DNA (72 percent) is located within plaques in AD brains (but only 24 percent in normals). David Cribbs has confused the two pairs of values, i.e., made invalid comparisons. Also, he seemingly overlooks the fact that APOE-ε4 alone is neither necessary nor sufficient to cause AD.
2. These data revealing the very precise localization of HSV1 DNA in AD amyloid plaques need to be viewed in conjunction with our previous data showing that the virus causes accumulation of Aβ in infected cell cultures and mouse brains (Wozniak et al., 2007): the two sets of information strongly support causality, not merely association.
3. Aβ production (and AD-like tau, which is formed, too; Wozniak et al., 2009) might be protective—but only initially: we have preliminary data suggesting that the cell might produce Aβ in an abortive attempt to combat the virus, but this eventually results in overproduction and toxicity of the peptide products.
4. Rudy Castellani et al. mention that oxidative stress precedes amyloid deposition. Oxidation/inflammation in brain might well explain the effects of HSV1; indeed, it is known that the virus induces this phenomenon, as well as being reactivated by inflammation, but some agent or event has to be invoked as the initial cause of oxidation/inflammation, and HSV1 (with APOE-ε4) is surely the prime candidate as it is present in such a high proportion of elderly brains.
5. David Cribbs mentions clinical trials of antivirals to address more definitively the involvement of HSV1 in AD. We have preliminary data suggesting that antivirals inhibit Aβ and AD-like tau formation in infected cell cultures (to be published). We hope now, if funding allows, to investigate antiviral effects on infected mouse brains and to initiate clinical trials of antiviral agents in humans, as well to examine the effects of HSV1 on synaptic function.
Wozniak MA, Itzhaki RF, Shipley SJ, Dobson CB.
Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation.
Neurosci Lett. 2007 Dec 18;429(2-3):95-100.
Wozniak MA, Frost AL, Itzhaki RF.
Alzheimer's disease-specific tau phosphorylation is induced by herpes simplex virus type 1.
J Alzheimers Dis. 2009;16(2)
I agree with most of the comments from the above contributors. The experiments of Wozniak et al. suggest that HSV-1 may be a cofactor in the development of AD. In itself, this is a significant finding that follows previous work from Ruth Itzhaki’s group, and in view of the massive problem of AD it is worthy of further study. If, as suggested by Keith Crutcher, the research community views this work with apathy or antagonism, then there is something seriously wrong. The challenge now is to investigate the validity of the hypothesis, through independent confirmation of the findings of Wozniak et al., and by carrying out further experiments, including those suggested by David Cribbs. Ignoring the possibility that HSV-1 causes or contributes to AD cannot be an option.
In this recent publication, Wozniak, Mee, and Itzhaki present exciting new data that elucidate the direct relationship between herpes simplex type 1 (HSV1) DNA and amyloid plaques in human brains, mostly of Alzheimer’s patients. Using sensitive in situ polymerase chain reaction, they detected HSV1 DNA in coincidence with pathological amyloid plaques. This striking localization of the viral DNA within the amyloid plaques of Alzheimer’s brains strongly suggests a relationship between the development of the amyloid plaques and the presence of the viral DNA in the brain.
Dr. Itzhaki and her collaborators have been investigating the etiology of Alzheimer disease for many years. This recent publication is one of many high-quality studies in which very sensitive biochemical, histological, and virological techniques were used to assess and identify the functional relationship between latent HSV1 DNA that is present in brains and Alzheimer disease. Their studies, which are novel and ground-breaking, give a rationale for more extensive work in animal models. For example, mice transgenic for ApoE could, when infected with HSV1, produce AD pathology. The development of a model such as this would allow the identification and detection of early molecular events and lead to drug development studies for AD.