Herpes and AD—Virus Hitches Ride with APP

In this month's Aging Cell, researchers show that the herpes simplex virus (HSV), traveling away from the neuronal cell body along axons, is associated with the amyloid precursor protein (APP). This finding offers some new insights into the epidemiologic connection between Alzheimer's disease and HSV-1 (see ARF related news story).

Elaine Bearer and colleagues working at Brown University, Providence, Rhode Island, and the Marine Biology Laboratory, Woods Hole, Massachusetts, noticed the connection when studying transport of new viral particles in the giant axon of the squid. HSV normally travels retrogradely during its infection phase; then, following viral replication, new viral particles travel anterogradely back down neural processes to be released into the mucosal membranes. What determines transport direction is unclear, but recruitment of specific motors by viral proteins may be the key, because particles stripped of their glycoprotein-rich envelope travel only retrogradely.

When first author Prasanna Satpute-Krishnan and colleagues injected squid axons with green fluorescent protein-labeled mature viral particles from infected cytoplasm, the particles moved rapidly in an anterograde direction. To determine what surface proteins contribute to the direction of motion, Satpute-Krishnan examined the particles by electron microscopy, finding that the capsid is surrounded by a protein envelope, which in turn is encased in another membrane. The latter is most likely post-Golgi secretory vesicles, according to the authors. Such vesicles are normally involved in transporting molecules to axonal termini.

APP matures in the Golgi apparatus and has been implicated as a transport motor receptor (see ARF related news story). To see if APP may be present in the viral particles, the authors separated the capsids from their membrane components, then probed the latter for APP. Antibodies to either N- or C-termini of APP revealed an abundant 120 kDa protein in this fraction. In fact, Satpute-Krishnan shows that there are between one thousand and one million APPs per virion, about the same as for true viral proteins, such as the gD envelope protein or the VP22 protein of the viral tegument.

The relationship between APP and HSV is not well understood. One theory links the two with ApoE, which is both a risk factor for AD and binds to gB, a glycoprotein of the viral envelope. But the present findings "provide an alternative hypothesis," according to the authors, who propose that abnormal location, accumulation and processing of APP may result from HSV infection.—Tom Fagan

Comments

  1. The presence of HSV in brain has been correlated previously with Alzheimer's disease (Itzhaki and Dobson, 2002). The paper by Satpute-Krishnan et al. provides a clue for understanding this relationship in the form of a molecular interaction between HSV and APP in anterograde transport in neurons. This interaction was demonstrated using the classic model of the giant squid axon. This is an elegantly executed and exciting study that opens up many new avenues for further exploring of the biological function of APP in neurons, and determining the role of HSV in Alzheimer's disease. Although generalized transport mechanisms are conserved between invertebrates and vertebrates, it will be essential to demonstrate a similar HSV-APP interaction in neurons of human or mammalian brain, in order to further establish the relevance of these findings to Alzheimer's disease.

    References:

    Itzhaki RF, Dobson CB. Alzheimer's disease and herpes. CMAJ. 2002 Jul 9;167(1):13. PubMed.

    View all comments by Inez Vincent

  2. The paper by Satpute-Krishnan et al. links the seemingly disparate worlds of amyloid and herpesviruses via the more neutral domain of the giant axon of the squid—the fons et origo of our knowledge about nerve conduction/impulses. The aim was to investigate the mechanism whereby HSV1 in the neuronal cell body, when reactivated from its normal state of latency within the human peripheral nervous system, travels along the axon by anterograde transport to its site of entry into the host at the mucosal epithelium. The virus is shed there, probably in everybody infected with HSV1 (not, as the authors imply, just in those people—some 20-40 percent—who develop cold sores), and is thus transmitted in the saliva to another host.

    The paper suggests that the presence of HSV1 could affect the transport of APP, leading to its misplacement and that of its hydrolysis products, causing synaptic and neuronal dysfunction of the type seen in AD, and this could account for the pathogenic effects of the virus. The association between HSV1 and APP is an exciting one. It will be interesting to see whether HSV1 present in more physiologically relevant cells—neurons rather than Vero (i.e., monkey kidney) cells—is associated with APP, whether this APP is required for neuronal transport of the virus, and whether its own transport and degradation are affected.

    Of course, the above study is very probably appropriate for examining HSV1 transport in the human PNS and relevant to the high proportion (certainly in the age group of those afflicted with AD) of people infected with HSV1, all of whom carry the virus in their PNS for the rest of their lives. What happens in the CNS, and how ApoE enters this scheme is unknown, but it is certainly consistent with our discoveries that HSV1 resides in the brain of a high proportion of elderly people (Jamieson et al., 1991), and that it confers a high risk of AD when in ApoE-ε4 carriers, accounting for about 60 percent of those we examined (Itzhaki et al., 1997; Lin et al., 1998). It links also with our finding that HSV1 infection of cultured human neuroblastoma cells causes an accumulation of a C-terminal 55Kda fragment of APP (Dobson et al., 2002) (although, as expected, synthesis of most other cell protein is impaired). Further, a study by Benboudjema et al., 2003 describes another association between HSV1 and APP: The viral protein US11 co-localizes and interacts with the cellular protein PAT1, which is involved in transport of APP. Thus, there might be multiple interactions between HSV1 and APP. Indeed, we think that all these associations, together with the results described below, along with our hypothesis relating to ApoE-ε4, may be relevant rather than are alternative mechanisms.

    The effects of HSV1 on synaptic function appear not to have been studied, so the hypothesis of Satpute-Krishnan et al. remains to be tested. However, it is known and highly relevant to AD that synaptic dysfunction is closely correlated with extent of memory impairment—in marked contrast to the absence of correlation with amount of amyloid plaques or of neurofibrillary tangles. Thus, the study by Satpute-Krishnan et al. might indicate a cause not only of cognitive decline in AD, but also of plaque formation, an aspect which so far seems to have been overlooked by those who maintain that Aβ deposition is the primary event in the disease.

    Interestingly, another study showed a link between HSV1 and β-amyloid, in that there is a striking homology between sequences in the latter and a viral glycoprotein, gB, and the authors suggested that gB might act as a seed for amyloid deposition (Cribbs et al., 2000). Further, results of three recent epidemiological studies (Verreault et al., 2001; Holmes et al., 2003; Strandberg et al., 2003) are consistent with a role for infectious agents in AD, two suggesting that systemic infections (specifically HSV1 plus two other herpesviruses, in one of the studies) result in cognitive decline in the elderly, and a third study, that vaccination against various viruses protects against AD. In yet another approach, a study on ApoE-transgenic mice has shown that a few days after infection with HSV1, the viral load in brain is much higher in ApoE-ε4 than in ε3 animals, indicating an earlier entry of virus or greater replication (Burgos et al., 2003).

    We, therefore, propose one mechanism leading to AD: Peripheral infections cause entry of cytokines into the brain and consequent inflammation; the latter reactivates latent HSV1 in brain and damage then ensues—perhaps through disturbed axonal transport of APP and deposition of β-amyloid. We also propose that the extent of viral spread and possibly of repair of viral damage, i.e., the degree of damage, depends on ApoE genotype. The joint role of HSV1 and ApoE-ε4 in AD is strongly, if indirectly, supported by our studies (Itzhaki et al., 1997; Lin et al., 2001; Wozniak et al., 2002 and 2003), also by Corder et al., 1998 on diverse diseases, including cold sores, of known pathogen cause, which show that ApoE determines the outcome of or susceptibility to infection, probably by competing with the pathogen for entry into cells. If HSV1 reaches the brain earlier in ApoE-ε4 carriers, so that at least initially there is a greater viral load in brain, this would account for their earlier age of onset of AD and the greater extent of β-amyloid deposition. An examination of HSV1 effects on synaptic function, and a detailed investigation of ApoE-transgenic mice, for both of which we hope (still) to obtain funding, might elucidate the precise mechanisms leading to the development of AD.

    References:

    Benboudjema L, Mulvey M, Gao Y, Pimplikar SW, Mohr I. Association of the herpes simplex virus type 1 Us11 gene product with the cellular kinesin light-chain-related protein PAT1 results in the redistribution of both polypeptides. J Virol. 2003 Sep;77(17):9192-203. PubMed.

    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. PubMed.

    Corder EH, Robertson K, Lannfelt L, Bogdanovic N, Eggertsen G, Wilkins J, Hall C. HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nat Med. 1998 Oct;4(10):1182-4. PubMed.

    Cribbs DH, Azizeh BY, Cotman CW, Laferla FM. Fibril formation and neurotoxicity by a herpes simplex virus glycoprotein B fragment with homology to the Alzheimer's A beta peptide. Biochemistry. 2000 May 23;39(20):5988-94. PubMed.

    Dobson CB, Itzhaki RF, Shipley S. Abnormal processing of amyloid precursor protein after acute infection of human neuroblastoma cells with herpes simplex virus type 1. Neurobiol Aging. 2002 Jul-Aug; 23(Suppl 1):394.

    Holmes C, El-Okl M, Williams AL, Cunningham C, Wilcockson D, Perry VH. Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2003 Jun;74(6):788-9. PubMed.

    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. PubMed.

    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. PubMed.

    Lin WR, Graham J, MacGowan SM, Wilcock GK, Itzhaki RF. Alzheimer's disease, herpes virus in brain, apolipoprotein E4 and herpes labialis. Alzheimer's Rep. 1998;1:173-8.

    Lin WR, Wozniak MA, Esiri MM, Klenerman P, Itzhaki RF. Herpes simplex encephalitis: involvement of apolipoprotein E genotype. J Neurol Neurosurg Psychiatry. 2001 Jan;70(1):117-9. PubMed.

    Strandberg TE, Pitkala KH, Linnavuori KH, Tilvis RS. Impact of viral and bacterial burden on cognitive impairment in elderly persons with cardiovascular diseases. Stroke. 2003 Sep;34(9):2126-31. PubMed.

    Verreault R, Laurin D, Lindsay J, De Serres G. Past exposure to vaccines and subsequent risk of Alzheimer's disease. CMAJ. 2001 Nov 27;165(11):1495-8. PubMed.

    Wozniak MA, Faragher EB, Todd JA, Koram KA, Riley EM, Itzhaki RF. Does apolipoprotein E polymorphism influence susceptibility to malaria?. J Med Genet. 2003 May;40(5):348-51. PubMed.

    Wozniak MA, Itzhaki RF, Faragher EB, James MW, Ryder SD, Irving WL, . Apolipoprotein E-epsilon 4 protects against severe liver disease caused by hepatitis C virus. Hepatology. 2002 Aug;36(2):456-63. PubMed.

    View all comments by Curtis Dobson

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References

News Citations

  1. Neurons and Glia Found to Die by Apoptosis in Human Herpes Encephalitis
  2. Suspects for Aβ Generation Spotted Together, En Route to Nerve Terminal

Further Reading

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Primary Papers

  1. 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. PubMed.

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