Three interesting recent papers add further support to the proposition that herpes simplex virus type 1 (HSV1) plays a major role in many cases of Alzheimer’s disease (AD). The first, by Piacentini et al. (1), found that HSV1 infection of primary cultures of rat embryonic neurons causes hyperexcitability and disrupts intraneuronal Ca2+ homeostasis, as shown by the influx of large amounts of Ca2+. These changes, caused by virus binding to the neuronal membranes, lead to Ca2+-dependent APP phosphorylation and increased intracellular Aβ production—the latter in agreement with our finding that HSV1 increases Aβ accumulation in cultured cells and in brains of infected mice, and increases levels of β- and γ-secretase (2). (The increase in β-secretase which leads to the increased Aβ has since been shown to occur via activation of PKR and eIF2α [Ill-Raga et al., under revision]). As Piacentini et al. point out, loss of Ca2+ homeostasis and its effects on APP metabolism are notable features of AD, and they state that their findings “are compatible with the co-factorial role for HSV1 in...  Read more

Three interesting recent papers add further support to the proposition that herpes simplex virus type 1 (HSV1) plays a major role in many cases of Alzheimer’s disease (AD). The first, by Piacentini et al. (1), found that HSV1 infection of primary cultures of rat embryonic neurons causes hyperexcitability and disrupts intraneuronal Ca2+ homeostasis, as shown by the influx of large amounts of Ca2+. These changes, caused by virus binding to the neuronal membranes, lead to Ca2+-dependent APP phosphorylation and increased intracellular Aβ production—the latter in agreement with our finding that HSV1 increases Aβ accumulation in cultured cells and in brains of infected mice, and increases levels of β- and γ-secretase (2). (The increase in β-secretase which leads to the increased Aβ has since been shown to occur via activation of PKR and eIF2α [Ill-Raga et al., under revision]). As Piacentini et al. point out, loss of Ca2+ homeostasis and its effects on APP metabolism are notable features of AD, and they state that their findings “are compatible with the co-factorial role for HSV1 in the pathogenesis of AD suggested by previous findings” (1). Another paper by the same group (3) describes HSV1-induced APP processing that generates multiple neurotoxic fragments which, they speculate, would accumulate on repeated reactivation of HSV1, and thus play a co-factorial role in AD.

Piacentini et al. attribute Aβ production to the HSV1-induced hyperexcitability and Ca2+-dependent APP phosphorylation, but it was not directly caused by virus-membrane binding, for they found that UV-inactivated HSV1 (which binds to and enters cells but does not replicate) did not produce Aβ. In fact, our studies on Vero cells infected with mutant HSV1 indicate that initiation of Aβ formation, and of AD-like tau phosphorylation (p-tau), occur during or after the viral IE protein synthesis stage that immediately precedes viral DNA replication (in preparation); consistently, we found that antiviral agents that stop HSV1 DNA synthesis greatly decrease virus-induced increases in Aβ and p-tau in both Vero and human neuroblastoma cells. The stage(s) at which viral damage occurs is relevant to the possible usage of anti-herpes agents for treating AD, because these agents would prevent HSV1-induced Aβ and p-tau formation only if such damage depends on viral DNA synthesis. However, by preventing HSV1 replication, anti-herpes agents would stop formation and spread of new viruses, thereby precluding any virus binding to the membranes of uninfected cells, and, in fact, reducing greatly all types of viral damage—while causing no harm to normal cell components.

The second paper, by Lukiw et al. (4), investigated micro-RNA-146a, an miRNA associated with innate immunity. Expression of this miRNA increases after onset of neuropathology in AD transgenic mouse models, and its levels are higher in certain regions of AD brains than in those of age-matched controls (5). Lukiw et al. (4) found that HSV1 infection upregulated miRNA-146a in co-cultures of primary neuronal and glial cells, and that the antiviral agent acyclovir, which specifically targets replicating virus, significantly reduced levels of this miRNA. The same occurred with soluble Aβ42 (although the authors seem not to have checked quantitatively for a toxic effect of Aβ42 rather than a direct antiviral effect). The authors suggest that Aβ42 might thus act as an antiviral agent in HSV1-infected brains, broadly in line with the study by Soscia et al. (6) proposing that the peptide has antimicrobial action. The seemingly paradoxical properties (protective and destructive) of Aβ and its products could be explained, as we suggested, by its having initially a protective action but subsequently being overproduced (7). An alternative possibility—that it is induced by the virus to aid its own replication—seems less likely in view of these data.

The third paper, by Porcellini et al. (8), suggests that the strong polymorphism association of eight genes with AD results in a genetic signature that might affect individual brain susceptibility to infection by the herpes virus family during aging, leading to neuronal loss, inflammation, and Aβ deposition. Data from our lab, and from studies of others on HSV1-infected ApoE-transgenic mice, suggest that ApoE modulates the severity of damage caused by HSV1. Perhaps in humans, ApoE determines also the age at which the virus travels from the peripheral nervous system to the brain, with entry occurring earlier in ApoE-ε4 carriers. However, it seems not to determine susceptibility to infection of brain, as human carriers of all ApoE genotypes can harbor HSV1 in brain (9), and in HSV1-infected ApoE-ε3-transgenic mice, the virus does enter the brain, albeit at lower rates than in ApoE-ε4 animals (10,11). Nonetheless, the hypothesis of Porcellini et al., like the data cited here, supports a role for HSV1 (in concert with ApoE-ε4) in AD. Hopefully, these and previous studies will encourage the AD community at least to ponder that possibility!

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

2. Wozniak MA, Itzhaki RF, Shipley SJ, Dobson CB. (2007) Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation. Neurosci Lett 429, 95-100. Abstract

3. De Chiara G, Marcocci ME, Civitelli L, Argnani R, Piacentini R, Ripoli C, Manservigi R, Grassi C, Garaci E, Palamara AT. APP processing induced by herpes simplex virus type 1 (HSV-1) yields several APP fragments in human and rat neuronal cells. PLoS One 5, e13989. Abstract

4. Lukiw WJ, Cui JG, Yuan LY, Bhattacharjee PS, Corkern M, Clement C, Kammerman EM, Ball MJ, Zhao Y, Sullivan PM, Hill JM. (2010) Acyclovir or Abeta42 peptides attenuate HSV-1-induced miRNA-146a levels in human primary brain cells. Neuroreport 21, 922-7. Abstract

5. Li YY, Cui JG, Hill JM, Bhattacharjee S, Zhao Y, Lukiw WJ. (2010) Increased expression of miRNA-146a in Alzheimer's disease transgenic mouse models. Neurosci Lett 487, 94-8. Abstract

6. Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, Burton MA, Goldstein LE, Duong S, Tanzi RE, Moir RD. (2010) The Alzheimer's Disease-Associated Amyloid beta-Protein Is an Antimicrobial Peptide. PLoS One 5, e9505. Abstract

7. Wozniak MA, Itzhaki RF. (2010) Antiviral agents in Alzheimer's disease: hope for the future? Therapeutic Advances in Neurological Disorders 3, 141-52. Abstract

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

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

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

11. Burgos JS, Ramirez C, Sastre I, Valdivieso F. (2006) Effect of apolipoprotein E on the cerebral load of latent herpes simplex virus type 1 DNA. J Virol 80, 5383-7. Abstract

View all comments by Ruth Itzhaki

Joseph Prandota at the University Medical School in Wroclaw, Poland, suggests that Toxoplasma gondii (T. gondii), the parasitic protozoa hosted in cats, which causes cerebral toxoplasmosis (CT), may be implicated in the pathogenesis of Alzheimer's disease (AD).

Prandota states that T. gondii affects chromatin structure and may cause dysregulation of the host cell cycle. Moreover, it seems that the accumulation of iron in senile plaques reflects a defense of the host against T. gondii because this transition metallic ion is necessary for proliferation of tachyzoites, which are part of the protozoan's life cycle.

Prandota observes that the beneficial effects of ibuprofen in patients with AD, which restored cellular immunity, decreased production of proinflammatory cytokines, nitric oxide, and amyloid-β, and reduced lipid peroxidation and free radical generation, are consistent with the suggestion that congenital and/or acquired chronic latent CT plays a role in neurodegeneration.

References:
Prandota J. Metabolic, immune, epigenetic, endocrine and phenotypic abnormalities found in individuals with autism spectrum disorders, Down syndrome and Alzheimer disease may be caused by congenital and/or acquired chronic cerebral toxoplasmosis. Research in Autism Spectrum Disorders, Volume 5, Issue 1, January-March 2011, pp. 14-59. Abstract

View all comments by David Corbin