In this innovative study, Miller and Federoff report new evidence intimately linking apolipoprotein E (ApoE) and herpes simplex virus type 1 (HSV1), which strengthens the case that the two factors together are important in Alzheimer disease (AD).

The authors investigated the effect of ApoE on the expression of specific genes during the two types of infection that HSV1 can cause: acute and latent. In the former, viral gene expression occurs, the virus replicates, and whole virus particles are produced which spread from cell to cell, eventually causing cell death. The authors studied the so-called immediate early (IE) genes. During latency, gene expression is limited to the latency-associated transcripts (LAT), which were studied by the authors; no viruses are produced, and no obvious ill effects occur in the host cell (thus ensuring host survival and thereby that of the virus).

In humans, latent HSV1 resides lifelong in the trigeminal ganglia of some 80-90 percent of people, but it can reactivate during stress or immunosuppression, leading to productive infection....  Read more

In this innovative study, Miller and Federoff report new evidence intimately linking apolipoprotein E (ApoE) and herpes simplex virus type 1 (HSV1), which strengthens the case that the two factors together are important in Alzheimer disease (AD).

The authors investigated the effect of ApoE on the expression of specific genes during the two types of infection that HSV1 can cause: acute and latent. In the former, viral gene expression occurs, the virus replicates, and whole virus particles are produced which spread from cell to cell, eventually causing cell death. The authors studied the so-called immediate early (IE) genes. During latency, gene expression is limited to the latency-associated transcripts (LAT), which were studied by the authors; no viruses are produced, and no obvious ill effects occur in the host cell (thus ensuring host survival and thereby that of the virus).

In humans, latent HSV1 resides lifelong in the trigeminal ganglia of some 80-90 percent of people, but it can reactivate during stress or immunosuppression, leading to productive infection. This process occurs repeatedly, with ApoE4 carriers being particularly susceptible to overt reactivation, i.e., cold sores [1,2]. Many elderly people harbor latent HSV1 in brain, too [3], and they have a greater risk of developing AD if they carry an ApoE4 allele [1,2]. The ways in which HSV1 and ApoE interact are unclear, and it is imperative to determine their interaction for elucidating the development of AD.

Miller and Federoff used primary neuronal cultures from ApoE-transgenic and ApoE-knockout mice to assess viral IE gene expression, and found the highest level in cells from KO and ApoE4 mice. Examination of the Tgs showed that LAT expression was least in KO and ApoE4 animals. The authors conclude that in the latter, the virus remains longer than the usual 5 or so days in the replicative phase prior to latency, thus prolonging lytic infection and cell death, and that the data support the concept that HSV1 in brain and ApoE4 synergistically promote neuronal death—death occurring in AD. Interestingly, a study by Hill et al. [4] showed similarly the importance of ApoE in the response to HSV1, latency being less efficiently established in the trigeminal ganglia of ApoE KO mice than in control animals. The Miller-Federoff data are consistent also, as the authors point out, with those of Perng et al. [5], indicating that LAT expression in vitro blocks apoptotic death induced by various insults.

Two major questions remain:

1. What is the critical damage relevant to AD caused by HSV1 and ApoE4? Miller and Federoff suggest that the greater vulnerability of infected neurons in E4 carriers leads to Aβ-mediated synaptic and cellular dysfunction. Our current studies (submitted) show a direct effect of HSV1 on amyloid aggregation and on abnormal phosphorylation of tau, either of which could cause such damage. Possibly, both indirect and direct effects of HSV1 are relevant to AD.

2. How do HSV1 and ApoE interact? Miller and Federoff suggest that as viral load was independent of ApoE in their neuronal cultures, isoform-specific damage occurs after virus entry into cells. However, in the sole other study of HSV1-infected ApoE-transgenic mice, by Burgos et al. [6], viral load in brain was highest in ApoE4 animals. Possibly, the different routes of injection and different tissues account for this. From our cell studies, we have invoked another mechanism: that virus and protein compete for common receptors in the cell surface, the isoform with the weakest binding—in this case ApoE4—allowing greater viral entry, spread, and damage. This idea is supported by investigations of selected infectious diseases [7] in which the micro-organism binds to an ApoE receptor; these show that ApoE indeed influences severity of disease. Clearly, the answers must await further work by the authors—which we look forward to very keenly—especially on the CNS of their animals.

Finally, this study on HSV1 and the influence of ApoE on outcome of infection is most welcome. There is a paucity of publications owing to lack of funding and an inexplicable prejudice against a role for micro-organisms in AD. It is gratifying that similar “heresies” in the past, relating micro-organisms to certain cancers and to stomach ulcers, were eventually proved correct.

References:
1. Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer's disease. Lancet. 1997 Jan 25;349(9047):241-4. Abstract

2. Lin, W.R., Graham, J., MacGowan, S.M., Wilcock, G.K. & Itzhaki, R.F. Alzheimer’s disease, herpes virus in brain, apolipoprotein E4 and herpes labialis. Alzheimer's Reports 1, 173-178 (1998).

3. Jamieson GA, Maitland NJ, Wilcock GK, Craske J, Itzhaki RF. Latent herpes simplex virus type 1 in normal and Alzheimer's disease brains. J Med Virol. 1991 Apr;33(4):224-7. Abstract

4. Bhattacharjee PS, Neumann DM, Stark D, Thompson HW, Hill JM. Apolipoprotein E modulates establishment of HSV-1 latency and survival in a mouse ocular model. Curr Eye Res. 2006 Sep;31(9):703-8. Abstract

5. Perng GC, Jones C, Ciacci-Zanella J, Stone M, Henderson G, Yukht A, Slanina SM, Hofman FM, Ghiasi H, Nesburn AB, Wechsler SL. Virus-induced neuronal apoptosis blocked by the herpes simplex virus latency-associated transcript. Science. 2000 Feb 25;287(5457):1500-3. Abstract

6. Burgos JS, Ramirez C, Sastre I, Bullido MJ, Valdivieso F. ApoE4 is more efficient than E3 in brain access by herpes simplex virus type 1. Neuroreport. 2003 Oct 6;14(14):1825-7. Abstract

7 Itzhaki RF, Wozniak MA. Herpes simplex virus type 1, apolipoprotein E, and cholesterol: a dangerous liaison in Alzheimer's disease and other disorders. Prog Lipid Res. 2006 Jan;45(1):73-90. Epub 2005 Dec 15. Review. Abstract

View all comments by Ruth Itzhaki

The role of infectious disease, and particularly the common neurotrophic virus herpes simplex type 1 (HSV-1), in Alzheimer disease (AD) has been relatively neglected. The case for a role of HSV-1 is growing stronger with this report by Miller and Federoff.

HSV-1 is the cause of the common cold sore, and predicted to infect 85 percent of Americans. After infecting the cell of the lip, HSV secondarily enters the sensory processes of neurons and travels within them to the trigeminal ganglion, where it either enters latency or replicates. From the bipolar neurons in the trigeminal ganglion, HSV has a straight shot to the brainstem, and from there it's only a hop, skip, and a jump to the cortex or hippocampus of the brain.

HSV virions are associated with high levels of the amyloid precursor protein (APP; see Satpute-Krishnan et al., 2003), which produces the toxic peptide fragments present in senile plaques. We found recently that APP is sufficient to hitch viral-sized particles to neuronal transport machinery (Satpute-Krishnan et al., 2006). Thus cellular APP could hitch...  Read more

The role of infectious disease, and particularly the common neurotrophic virus herpes simplex type 1 (HSV-1), in Alzheimer disease (AD) has been relatively neglected. The case for a role of HSV-1 is growing stronger with this report by Miller and Federoff.

HSV-1 is the cause of the common cold sore, and predicted to infect 85 percent of Americans. After infecting the cell of the lip, HSV secondarily enters the sensory processes of neurons and travels within them to the trigeminal ganglion, where it either enters latency or replicates. From the bipolar neurons in the trigeminal ganglion, HSV has a straight shot to the brainstem, and from there it's only a hop, skip, and a jump to the cortex or hippocampus of the brain.

HSV virions are associated with high levels of the amyloid precursor protein (APP; see Satpute-Krishnan et al., 2003), which produces the toxic peptide fragments present in senile plaques. We found recently that APP is sufficient to hitch viral-sized particles to neuronal transport machinery (Satpute-Krishnan et al., 2006). Thus cellular APP could hitch invading HSV virions to neuronal motors and redistribute the virus throughout the brain.

Other evidence also supports a link between AD and HSV. HSV genomic DNA is found in human brains in areas affected by AD (Jamieson et al., 1991 and 1992), and there is an epidemiological correlation between AD with the ApoE4 allele and HSV (Itzhaki et al., 2001). Hence HSV-1 could play a role in risk or progression of AD.

In the Miller and Federoff paper, a set of transgenic mice carrying either no ApoE gene or one or the other of the three major human alleles were tested for viral behavior. Significantly, mice with the ApoE4 allele expressed higher levels of the viral early genes and less of the latency gene. If this also occurs in humans carrying the ApoE4 allele, they would have more frequent reactivations of the virus with more virus emerging from latently infected cells in the brain over time. Such chronic viral emergence over time could cause loss of neurons as that seen in AD. The documented physical association of virus with APP and with ApoE would result in mislocalization of these proteins within the brain and thereby possibly induce abnormal proteolysis and plaque formation.

Since HSV replication can be suppressed with anti-viral therapy, these separate and supportive results from three different labs—the Federoff, Itzhaki, and Bearer labs—suggest an infectious mechanism for AD progression.

References:
Satpute-Krishnan P, DeGiorgis JA, Bearer EL. Fast anterograde transport of herpes simplex virus: role for the amyloid precursor protein of Alzheimer's disease. Aging Cell. 2003 Dec;2(6):305-18. Abstract

Satpute-Krishnan P, DeGiorgis JA, Conley MP, Jang M, Bearer EL. A peptide zipcode sufficient for anterograde transport within amyloid precursor protein. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16532-7. Abstract

Jamieson GA, Maitland NJ, Wilcock GK, Yates CM, Itzhaki RF. Herpes simplex virus type 1 DNA is present in specific regions of brain from aged people with and without senile dementia of the Alzheimer type. J Pathol. 1992;167(4):365-8. Abstract

Jamieson GA, Maitland NJ, Wilcock GK, Craske J, Itzhaki RF. Latent herpes simplex virus type 1 in normal and Alzheimer's disease brains. J Med Virol. 1991 Apr 1;33(4):224-7. Abstract

Itzhaki RF, Dobson CB, Lin WR, Wozniak MA. Association of HSV1 and apolipoprotein E-varepsilon4 in Alzheimer's disease. J Neurovirol. 2001 Dec;7(6):570-1. Abstract

View all comments by Elaine L. Bearer

AD is a common and complex disorder in which environmental and genetic factors are strongly involved. Major risk factors for the sporadic form include old age, family history of dementia, head injury, and apolipoprotein E ε4 (ApoE ε4). Recently, epidemiological data for a correlation between herpes infections and AD have been collected.

HSV-1 is neurotrophic and able to establish latency in humans. HSV-1 is latent in the peripheral nervous system of most populations. The first hypothesis that HSV-1 could be involved in the pathogenesis of AD was suggested by noting that the brain area damaged during HSV-1 encephalitis and affected early in AD is the temporal lobe. It was revealed that HSV-1 is present in latent form in the brains of a high proportion of elderly people and is a risk factor for ApoE ε4 positive AD cases.

HSV-1 was shown within amyloid deposits in the brains of patients with AD, but the role of HSV-1 in AD pathology remains a matter of controversy. The basic question concerns the mechanism of viral transport within CNS in the latency phase. The phenomenon...  Read more

AD is a common and complex disorder in which environmental and genetic factors are strongly involved. Major risk factors for the sporadic form include old age, family history of dementia, head injury, and apolipoprotein E ε4 (ApoE ε4). Recently, epidemiological data for a correlation between herpes infections and AD have been collected.

HSV-1 is neurotrophic and able to establish latency in humans. HSV-1 is latent in the peripheral nervous system of most populations. The first hypothesis that HSV-1 could be involved in the pathogenesis of AD was suggested by noting that the brain area damaged during HSV-1 encephalitis and affected early in AD is the temporal lobe. It was revealed that HSV-1 is present in latent form in the brains of a high proportion of elderly people and is a risk factor for ApoE ε4 positive AD cases.

HSV-1 was shown within amyloid deposits in the brains of patients with AD, but the role of HSV-1 in AD pathology remains a matter of controversy. The basic question concerns the mechanism of viral transport within CNS in the latency phase. The phenomenon of viral reactivation in neurons after trauma to the tissue they innervate, after systemic stimuli such as stress, hormonal, and nutritional factors is well-known, but the molecular mechanisms of HSV-1 reactivation in neurons and dissemination within CNS is unknown.

In the brains of patients with AD, a constant low level of HSV-1 replication may occur asymptomatically, but molecular mechanisms of HSV-1 transport within central nervous system in the latency are not known. The theory of the hematogenous dissemination of latent HSV-1 with involvement of ApoE or the transmission by promoting viral passage across the synapse has been discussed recently.

References:
Saunders AM, Strittmatter WJ, Schmechel D et al. Association of apolipoprotein E allele epsilon4 with late set familial and sporadic Alzheimer’s disease. Neurology 1993; 43: 1467-1472. Abstract

Satpute-Krishnan P, DeGiorgis JA, Bearer EL. Fast anterograde transport of Herpes Simplex Virus: Role for the amyloid precursor protein of Alzheimer’s disease. Aging Cell 2003; 2: 305-318. Abstract

Jamieson GA, Maitland NJ, Wilcock GK et al. Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J Med Virol 1991; 33: 224-7. Abstract

Itzhaki RF, Dobson CB. Alzheimer’s disease and herpes. CMAJ. 2002 Jul 9;167(1):13. No abstract available. Abstract

Itzhaki RF, Lin WR, Shang D et al. Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 1997; 349: 241-244. Abstract

Mori I, Kimura Y, Naiki H et al. Reactivation of HSV-1 in the brain of patients with familial Alzheimer’s disease. J Med Virol. 2004; 73 (4): 605-611. Abstract

Burgos JS, Ramirez C, Sastre I et al. Involvement of apolipoprotein E in the hematogenous route of herpes simplex virus type 1 to the central nervous system. J. Virology 2002; 76: 12394-12398. Abstract

View all comments by Anita Geppert