Three more papers supporting the concept of a viral involvement in AD have recently been published. Santana et al. (1) found, as we did, that Aβ accumulation occurred in HSV1-infected cultures. They used APP-transfected human neuroblastoma cells (SK-N-MC) and detected a sevenfold increase (over mock-infected) in Aβ two hours post-infection (p.i.), well before the start of viral DNA replication (at about four hours p.i.), whereas we detected an increase after about six hours (2). This apparent difference is probably due to our using a 10-fold lower HSV1 dose and/or to a cell-type difference (we used non-APP-transfected SH-SY5Y neuroblastoma cells). In fact, as Santana et al. point out, a much lower HSV1 dose is probably more relevant to “physiological” HSV1 infection.

Information about the stage of infection is important in relation to antivirals: Agents such as acyclovir (ACV) and foscarnet (FOS) act by preventing viral DNA replication, so if viral damage relevant to AD occurs before replication—say, during virus binding to or entry into the cell—these agents would reduce...  Read more

Three more papers supporting the concept of a viral involvement in AD have recently been published. Santana et al. (1) found, as we did, that Aβ accumulation occurred in HSV1-infected cultures. They used APP-transfected human neuroblastoma cells (SK-N-MC) and detected a sevenfold increase (over mock-infected) in Aβ two hours post-infection (p.i.), well before the start of viral DNA replication (at about four hours p.i.), whereas we detected an increase after about six hours (2). This apparent difference is probably due to our using a 10-fold lower HSV1 dose and/or to a cell-type difference (we used non-APP-transfected SH-SY5Y neuroblastoma cells). In fact, as Santana et al. point out, a much lower HSV1 dose is probably more relevant to “physiological” HSV1 infection.

Information about the stage of infection is important in relation to antivirals: Agents such as acyclovir (ACV) and foscarnet (FOS) act by preventing viral DNA replication, so if viral damage relevant to AD occurs before replication—say, during virus binding to or entry into the cell—these agents would reduce the damage only indirectly, by reducing the number of viral progeny and, hence, the extent of viral spread.

Santana et al. showed that FOS treatment did not visibly affect Aβ staining, even at the high concentration of 1.3 mM (1), suggesting that Aβ production induced by HSV1 is independent of viral DNA replication. Our recent experiments show similarly that HSV1-induced Aβ accumulation is viral DNA replication independent (Wozniak et al., submitted). We found that FOS and ACV decreased Aβ levels significantly (depending on the concentration used), but that levels were not reduced to those in mock-infected cells. The fact that Aβ level was reduced by FOS does contrast with the findings of Santana et al., but the result likely reflects our infection conditions (1 pfu/cell for 16 hours), which allow the virus to replicate and spread to additional cells; thus, the decrease we observe probably occurs through diminished viral spread.

The second paper, by Lerchundi et al. (3), examined the cleavage of tau in HSV1-infected cultures of neurons and astrocytes from embryonic or neonatal mice. Previously, they found that in mouse primary neuronal cultures, the virus reduced neuronal viability, caused neurite alterations and changes in cytoskeletal dynamics, and that these effects were prevented by 50 μM ACV treatment before or during infection (4,5). Also, HSV1 triggered hyperphosphorylation of tau at S202, T205, S396, and S404 (we subsequently confirmed phosphorylation at S202, S396, and S404, and detected it also at T212 and S214 [6]). Their recent study showed that HSV1 caused caspase-3-induced cleavage of tau at D421 (3), an occurrence associated with neurodegeneration. This cleavage, as well as the tau hyperphosphorylation, occurred during the first four hours p.i., and it was not significantly reduced by 50 μM ACV treatment, suggesting that these effects are independent of viral DNA replication. We, too, have investigated the effect of antiviral agents on tau phosphorylation, specifically phosphorylation at S214 and T212 (Wozniak et al., submitted). However, at these sites, unlike those examined by Lerchundi et al. (3), we found that 50 μM ACV reduces the HSV1-induced phosphorylation to the levels in mock-infected cells, suggesting that the phosphorylation at these sites is dependent on viral DNA replication. Thus, it appears that phosphorylation of tau by HSV1 is a complex process with both viral DNA replication-dependent and independent sites.

In the third paper, Cheng et al. (7) built on earlier findings (8) showing that HSV1 and amyloid precursor protein (APP) interact during transport of the virus. They show, using a comprehensive series of experiments, that the interaction between HSV1 and APP is specific (other similar proteins are less frequently associated with the virus) and meaningful (APP transport is slowed and APP location is altered in infected cells, thereby possibly affecting APP function).

All three papers stress that their data support a role of HSV1 in the development of AD, thus adding to the weight of evidence provided by earlier research (see review [9]) and three other recent studies on HSV1 and AD (10-12).

References:
1. Santana S, Recuero M, Bullido MJ, Valdivieso F, Aldudo J. Herpes simplex virus type I induces the accumulation of intracellular ß-amyloid in autophagic compartments and the inhibition of the non-amyloidogenic pathway in human neuroblastoma cells. Neurobiol Aging. 2011 Jan 25. Abstract

2. 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. Abstract

3. Lerchundi R, Neira R, Valdivia S, Vio K, Concha MI, Zambrano A, Otth C. Tau cleavage at D421 by caspase-3 is induced in neurons and astrocytes infected with herpes simplex virus type 1. J Alzheimers Dis. 2011 Jan 1;23(3):513-20. Abstract

4. Zambrano A, Solis L, Salvadores N, Cortés M, Lerchundi R, Otth C. Neuronal cytoskeletal dynamic modification and neurodegeneration induced by infection with herpes simplex virus type 1. J Alzheimers Dis. 2008 Jul;14(3):259-69. Abstract

5. Otth C et al. Journal of Neurochemistry. 2009;110:45.

6. 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):341-50. Abstract

7. Cheng SB, Ferland P, Webster P, Bearer EL. Herpes simplex virus dances with amyloid precursor protein while exiting the cell. PLoS One. 2011;6(3):e17966. Abstract

8. 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

9. Wozniak MA, Itzhaki RF. Antiviral agents in Alzheimer's disease: hope for the future? Ther Adv Neurol Disord. 2010 May;3(3):141-52. Abstract

10. Piacentini R, Civitelli L, Ripoli C, Marcocci ME, De Chiara G, Garaci E, Azzena GB, Palamara AT, Grassi C. HSV-1 promotes Ca(2+)-mediated APP phosphorylation and Aß accumulation in rat cortical neurons. Neurobiol Aging. 2010 Jul 31. Abstract

11. Lukiw WJ, Cui JG, Yuan LY, Bhattacharjee PS, Corkern M, Clement C, Kammerman EM, Ball MJ, Zhao Y, Sullivan PM, Hill JM. Acyclovir or Aß42 peptides attenuate HSV-1-induced miRNA-146a levels in human primary brain cells. Neuroreport. 2010 Oct 6;21(14):922-7. Abstract

12. Porcellini E, Carbone I, Ianni M, Licastro F. Alzheimer's disease gene signature says: beware of brain viral infections. Immun Ageing. 2010;7:16. Abstract

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