Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that remains latent in host neurons. Viral DNA replication is a highly structured process in which the redistribution of nuclear proteins plays an important role. Although tau is most widely known as a microtubule-associated protein found in a hyperphosphorylated state in the brains of patients with Alzheimer's disease (AD), this protein has also been detected at other sites such as the nucleolus. Here, we establish that HSV-1 infection gives rise to an increase in tau phosphorylation and that hyperphosphorylated tau accumulates in the nucleus, forming defined structures in HSV-1-infected neuronal cells reminiscent of the common sites of viral DNA replication. When tau expression in human neuroblastoma cells was specifically inhibited using an adenoviral vector expressing a short hairpin RNA to tau, viral DNA replication was not affected, indicating that tau is not required for HSV-1 growth in neuronal cells. Given that HSV-1 is considered a risk factor for AD, our results suggest a new way in which to understand the relationships between HSV-1 infection and the pathogenic mechanisms leading to AD.

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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.

Autophagy is a homeostatic process involved in the turnover or elimination of cytoplasmic components, damaged organelles, and protein aggregates via a lysosomal degradation mechanism. Autophagy also provides a mechanism of innate immunity, known as xenophagy, designed to protect cells from intracellular pathogens, but it may unfortunately be subverted to act as a pro-viral pathway facilitating the replication of certain viruses. Herpes simplex virus type I (HSV-1) is a neurotropic virus that remains latent in host neurons; it is the most common cause of sporadic viral encephalitis. Moreover, HSV-1 has been related to the pathogenesis of Alzheimer's disease. HSV-1 can modulate the autophagic process through a mechanism mediated by the viral protein ICP34.5. Here we report that HSV-1 induces a strong increase in GFP-LC3 and endogenous LC3 lipidation, and triggers the accumulation of intracellular autophagic compartments (mainly autophagosomes) without enhancing autophagic long-lived protein degradation in the late stages of infection. Autophagy inhibition mediated by ATG5 gene silencing had no effect on viral growth. The present results suggest that HSV-1 infection activates the host autophagic machinery and strongly controls the autophagic process, blocking the fusion of autophagosomes with lysosomes. These events might be important in the neurodegenerative process associated with HSV-1 infection.

Plasma Aβ levels are higher in individuals who have severe periodontal disease. The presence of periodontitis may modify the association between Aβ and cognitive impairment.

Objectives The role in dementia of systemic inflammation derived from periodontal disease is not fully elucidated. The objective of our study was to examine the impact of inflammation on the relationship between periodontitis and cognitive impairment. Methods We have designed a case (n = 171) and control (n = 131) study to determine the periodontal health status, grade of cognitive impairment/dementia and systemic inflammation level, the last being measured by analysis of 29 inflammatory biomarkers using multiplex techniques. Results At the time of sampling, 11 of the 29 inflammatory biomarkers were associated with cognitive impairment in patients with more severe periodontitis. However, the inflammatory response to severe periodontitis was more reduced (lower biomarker concentrations) in cases (with cognitive impairment or dementia) than in (cognitively healthy) controls, an unexpected finding. Conclusions Based on these results, we cannot confirm that systemic inflammation derived from periodontal disease plays a relevant role in the aetiology of cognitive impairment.

Herpes simplex virus (HSV) types 1 and 2 are neurotropic viruses that establish lifelong latent infections in neurons. Mounting evidence suggests that HSV-1 infection is involved in the pathogenesis of Alzheimer's disease (AD). The relationships between other herpesvirus infections and events associated with neurodegeneration have not, however, been extensively studied. The present work reports that HSV-2 infection leads to the strong accumulation of hyperphosphorylated tau and the amyloid-β peptides Aβ40 and Aβ42 (all major pathological hallmarks of AD) in human SK-N-MC neuroblastoma cells. Infection is also associated with a marked reduction in the amount of Aβ40 secreted and in the proteolytic fragments of the amyloid-β precursor protein (APP) (secreted APPα and the α-C-terminal fragment). These results indicate that HSV-2 infection inhibits the nonamyloidogenic pathway of APP processing and impairs Aβ secretion in these cells. In addition, HSV-2 induces the accumulation of intracellular autophagic compartments containing Aβ due to a failure in the late stages of autophagy. To our knowledge, this is the first report to show that HSV-2 infection strongly alters the tau phosphorylation state, APP processing, and autophagic process in human neuroblastoma cells, leading to the appearance of AD-like neurodegeneration markers.

Oxysterols are metabolites produced in the first step of cholesterol metabolism, which is related to neurodegenerative disorder. They can be detected by testing blood, plasma, serum, or cerebrospinal fluid. In this study, some cholesterol precursors and oxysterols were determined by gas chromatography coupled to mass spectrometry. The selected cholesterol-related compounds were desmosterol, lathosterol, lanosterol, 7α-hydroxycholesterol, 7β-hydroxycholesterol, 24(S)-hydroxycholesterol, 25-hydroxycholesterol, 7-ketocholesterol, and 27-hydroxycholesterol. A powerful method was developed and validated considering various analytical parameters, such as linearity index, detection and quantification limits, selectivity and matrix effect, precision (repeatability), and trueness (recovery factor) for each cholesterol-related compound. 7α-hydroxycholesterol, 7β-hydroxycholesterol, and desmosterol exhibited the lowest detection and quantification limits, with 0.01 and 0.03 µg/mL, respectively, in the three cases. 7-ketocholesterol and lathosterol showed matrix effect percentages between 95.5% and 104.8%, respectively (demonstrating a negligible matrix effect), and very satisfactory repeatability values (i.e., overall performance of the method). Next, the method was applied to the analysis of a very interesting selection of mouse plasma samples (9 plasma extracts of non-transgenic and transgenic mice that had been fed different diets). Although the number of samples was limited, the current study led to some biologically relevant conclusions regarding brain cholesterol metabolism.