Abstract
Animal models to study Alzheimer’s disease (AD) pathogenesis are under development. Since herpesviruses have been postulated to be capable of triggering the pathogenic process, AD animal models (mouse, pig, and non-human primates) should be controlled for the presence of these viruses. Only virus-free models allow studying the genetic factors and the effect of adding viruses. Roseoloviruses such as human herpesvirus 6 and the related viruses in the animals are the main topic of this commentary.
Numerous laboratories are developing non-modified and genetically modified murine, porcine, and non-human primate models to study Alzheimer’s disease (AD) pathogenesis, but little attention has been paid to natural herpesviruses that might affect the results. Numerous viruses and other microorganisms have been suspected to be involved in AD pathogenesis in the last years [1–3]. Recently, increased human herpesvirus 6A (HHV-6A) and HHV-7 were observed from subjects with AD compared with controls [4], although these results are controversial [5–7]. Although direct methods of viral detection do not suggest an association between HHV-6 and AD, this virus may be associated with an earlier “triggering” event, e.g., nucleation of amyloid-β (Aβ), or be present at copy numbers below the limit of laboratory detection [5].
HHV-6A/B are neurotropic viruses that are the largest cause of encephalitis and delirium in transplant patients [8]. HHV-6A infection was shown to accelerate the progression of AIDS (acquired immunodeficiency syndrome) in SIV (simian immunodeficiency virus)-infected macaques [9] and lead to neurological symptoms in marmosets [10]. HHV-6A/B and HHV-7 belong to the genus Roseolovirus of the subfamily Betaherpesvirinae, family Herpesviridae, and they are closely related to the murine roseolovirus (MRV) and the porcine cytomegalovirus/porcine roseolovirus (PCMV/PRV), which are ubiquitous in nature [11].
Since specific markers of human AD could not be reproduced in murine AD models [12] and since porcine brain biology is similar to human, pigs are believed to be a promising model. Whereas Göttingen Minipigs expressing mutant presenilin 1 (PS1), a marker of AD, showed no evidence of an AD phenotype [13], animals expressing mutant human PS1 and the amyloid precursor protein (APP) showed an increase in intraneuronal Aβ plaque formation [14]. Furthermore, a multi-cistronic vector encoding three AD-related genes with six well-characterized mutations: human APP, Tau, and PS1 was used to generate viable piglets [15].
The presence of MRV, also known as the mouse thymic virus (MTV), may influence the results in the murine models. MRV/MTV has been isolated from the brains of mice infected shortly after birth but not of those infected at the adult stage [11, 16]. No studies on the impact of MRV on the brain have been reported until now. On the other hand, several groups are currently working with transgenic mice expressing human CD46, the receptor of HHV-6. These animals therefore can be infected with HHV-6A to determine the impact on AD progression [17]. In order to optimize such transgenic mice as models for AD, they first should be rendered free of MRV/MTV.
In the case of PCMV/PRV, neurological signs have been reported in infected pigs; however detailed studies are still lacking [18, 19]. In pigs, congenital PCMV/PRV infections have been associated with multifocal lesions distributed throughout the cerebrum and cerebellum, and the virus has been isolated from the central nervous system [18]. Now that PCMV/PRV free colonies have been established by early weaning [20], it would be possible to study the effect of PCMV/PRV in vivo, in the pig.
Among the presently established animal models, non-human primates share the closest relationship with humans [21]. These models are mainly based on non-transgenic rhesus monkeys, stump-tailed macaques and others, the pathological changes were induced by chemicals or Aβ injections. In addition, a genetically modified marmoset model of AD is under development. In this model, PS1 is mutated using CRISPR/Cas [22]. In using these models, investigators should be aware that non-human primates also carry HHV-6 homologs which may interfere (for review, see [11]).
It is still unclear whether the murine, porcine, and non-human primate models will prove useful for the study of AD. However, these models should be free of the related MRV, PCMV/PRV, and simian HHV-6-like viruses, respectively, in order to obtain reliable results. Furthermore, they should also be free from other herpesviruses, particularly animal viruses similar to the human herpes simplex viruses-1/2 and varicella-zoster virus, that are postulated to be capable of triggering the AD pathogenic process. Such specified virus-free animals should be encouraged to be used. In addition, as new viruses, including herpesviruses have been constantly being discovered, early weaning, Caesarean delivery, or embryo transfer are proposed to exclude also undiscovered viruses which may affect AD in animal models and obtain the “virus-free” animals for further studies of AD. On the other hand, these “virus-free” animal models are also useful to study the influence of certain viruses including roseoloviruses on pathogenesis, if they are demonstrably virus-free and disease-free initially, and then experimentally inoculated with virus.
