Tau Cleavage at D-421 by Caspase-3 is Induced in Neurons and Astrocytes Infected with Herpes Simplex Virus Type 1

Institute of Clinical Microbiology, Faculty of Medicine, University Austral of Chile, Valdivia, Chile.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 01/2011; 23(3):513-20. DOI: 10.3233/JAD-2010-101386
Source: PubMed


Herpes Simplex Virus Type 1 (HSV-1) is ubiquitous, neurotropic, and the most common pathogenic causes of sporadic acute encephalitis in humans. Herpes simplex encephalitis is associated with a high mortality rate and significant neurological, neuropsychological, and neurobehavioral sequelae, which afflict patients for life. HSV-1 infects limbic system structures in the central nervous system and has been suggested as an environmental risk factor for Alzheimer's disease. However, the possible mechanisms that link HSV-1 infection with the neurodegenerative process are still largely unknown. In a previous study we demonstrated that HSV-1 triggers hyperphosphorylation of tau epitopes serine202/threonine205 and serine396/serine404 in neuronal cultures, resembling what occurs in neurodegenerative diseases. Therefore, the aim of the present study was to evaluate at the cellular level if another event associated with neurodegeneration, such as caspase-3 induced cleavage of tau, could also be triggered by HSV-1 infection in primary neuronal and astrocyte cultures. As expected, induction of caspase-3 activation and cleavage of tau protein at its specific site (aspartic acid 421) was observed by Western blot and immunofluorescence analyses in mice neuronal primary cultures infected with HSV-1. In agreement with our previous study on tau hyperphosphorylation, tau cleavage was also observed during the first 4 hours of infection, before neuronal death takes place. This tau processing has been previously demonstrated to increase the kinetics of tau aggregation in vitro and has also been observed in neurodegenerative pathologies. In conclusion, our findings support the idea that HSV-1 could contribute to induce neurodegenerative processes in age-associated pathologies such as Alzheimer's disease.

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    • "These increases were explained by increases in the relevant enzymes which, in the case of BACE, occur by HSV1-induced PKR activation and consequent phosphorylation of eIF2α (Ill-Raga et al., 2011). Further, infected primary neuronal and astrocyte cultures show AD-like caspase-3 activation and tau cleavage (Lerchundi et al., 2011). "
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    ABSTRACT: Abstract HSV1, when present in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE), has been implicated as a major factor in AD. It is proposed that virus is normally latent in many elderly brains but reactivates periodically (as in the peripheral nervous system) under certain conditions, for example stress, immunosuppression, and peripheral infection, causing cumulative damage and eventually development of AD. Diverse approaches have provided data that explicitly support, directly or indirectly, these concepts. Several have confirmed HSV1 DNA presence in human brains, and the HSV1-APOE-ε4 association in AD. Further, studies on HSV1-infected APOE-transgenic mice have shown that APOE-e4 animals display a greater potential for viral damage. Reactivated HSV1 can cause direct and inflammatory damage, probably involving increased formation of beta amyloid (Aβ) and of AD-like tau (P-tau) - changes found to occur in HSV1-infected cell cultures. Implicating HSV1 further in AD is the discovery that HSV1 DNA is specifically localised in amyloid plaques in AD. Other relevant, harmful effects of infection include the following: dynamic interactions between HSV1 and amyloid precursor protein (APP), which would affect both viral and APP transport; induction of toll-like receptors in HSV1-infected astrocyte cultures, which has been linked to the likely effects of reactivation of the virus in brain. Several epidemiological studies have shown, using serological data, an association between systemic infections and cognitive decline, with HSV1 particularly implicated. Genetic studies too have linked various pathways in AD with those occurring on HSV1 infection. In relation to the potential usage of antivirals to treat AD patients, acyclovir (ACV) is effective in reducing HSV1-induced AD-like changes in cell cultures, and valacyclovir, the bioactive form of ACV, might be most effective if combined with an antiviral that acts by a different mechanism, such as
    Frontiers in Aging Neuroscience 08/2014; 6:202. DOI:10.3389/fnagi.2014.00202 · 4.00 Impact Factor
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    • "Previously, we found that in vitro HSV-1 infection triggered a clear induction in TLR2 and TLR4 expression in astrocytes and showed increased levels of interferon regulatory factors IRF3 and IRF7 transcripts, as well as phospho-IRF3 protein indicating the activation of TLR-dependent pathways [21]. Furthermore, HSV-1 infection of neuronal and astrocytes cultures showed increased early neurodegenerative markers such as caspase-3 cleaved-(TauC3) and phosphorylated tau protein (pTau) [22] [23]. These findings were confirmed and further detailed by other groups identifying the protein kinases and the phosphorylation sites induced by the virus [24] and also showed that phospho-tau accumulation is dependent on HSV1 DNA replication [25]. "
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    ABSTRACT: Background: Currently, it is unclear whether asymptomatic recurrent reactivations of herpes simplex virus type 1 (HSV-1) occur in the central nervous systems of infected people, and if these events could lead to a progressive deterioration of neuronal function. In this context, HSV-1 constitutes an important candidate to be included among the risk factors for the development of neuropathies associated with chronic neuroinflammation. Objective: The aim of this study was to assess in vivo inflammatory and neurodegenerative markers in the brain during productive and latent HSV-1 infection using a mouse model of herpes simplex encephalitis. Methods: Neuroinflammation and neurodegeneration markers were evaluated in mice trigeminal ganglia and cerebral cortex during HSV-1 infection, by immunohistochemistry, western blot, and RT-PCR. Results: Neuronal ICP4 viral antigen expression indicative of a reactivation episode during asymptomatic latency of HSV-1 infection in mice was accompanied by upregulation of neuroinflammatory (toll-like receptor-4, interferon α/β, and p-IRF3) and early neurodegenerative markers (phospho-tau and TauC3). Conclusions: HSV-1 reactivation from latency induced neuroinflammatory and neurodegenerative markers in the brain of asymptomatic mice suggesting that recurrent reactivations could be associated with cumulative neuronal dysfunctions.
    Journal of Alzheimer's disease: JAD 12/2013; 39(4). DOI:10.3233/JAD-131706 · 4.15 Impact Factor
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    • "Other studies have now connected HSV-1 with the main neuropathological hallmarks of AD. For example, HSV-1 is now known to induce the accumulation of β-amyloid peptide (Aβ) [3],[4],[5],[6], hyperphosphorylated tau protein [7], [8], [9], [10] and immature autophagic vesicles [11], [12] in several infection models. Recently, the presence of IgM anti-HSV antibodies in serum - a marker of recent HSV reactivation - was also correlated with an increased risk of developing AD [13]. "
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    ABSTRACT: Mounting evidence suggests that Herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of Alzheimer's disease (AD). Previous work from our laboratory has shown HSV-1 infection to induce the most important pathological hallmarks of AD brains. Oxidative damage is one of the earliest events of AD and is thought to play a crucial role in the onset and development of the disease. Indeed, many studies show the biomarkers of oxidative stress to be elevated in AD brains. In the present work the combined effects of HSV-1 infection and oxidative stress on Aβ levels and autophagy (neurodegeneration markers characteristic of AD) were investigated. Oxidative stress significantly potentiated the accumulation of intracellular Aβ mediated by HSV-1 infection, and further inhibited its secretion to the extracellular medium. It also triggered the accumulation of autophagic compartments without increasing the degradation of long-lived proteins, and enhanced the inhibition of the autophagic flux induced by HSV-1. These effects of oxidative stress were not due to enhanced virus replication. Together, these results suggest that HSV-1 infection and oxidative damage interact to promote the neurodegeneration events seen in AD.
    PLoS ONE 10/2013; 8(10):e75842. DOI:10.1371/journal.pone.0075842 · 3.23 Impact Factor
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