There is some debate over whether persistent viral infection, such as by herpesvirus, contributes meaningfully to the onset and development of Alzheimer's disease. It would be a convenient explanation, given that many people with all of the lifestyle risk factors for neurodegeneration, such as being overweight and sedentary, do not in fact go on to develop Alzheimer's. The epidemiology is mixed, however, with some studies suggesting yes, some no. Some of the positive data suggests that use of antiviral drugs lowers the risk of Alzheimer's. More recent work argues that multiple different viral infections are required for a significant effect on Alzheimer's risk, which might explain why earlier epidemiology has produced conflicting results.
Meanwhile, researchers continue to explore the cellular biochemistry that might cause viral infection to increase production of amyloid-β, an anti-microbial peptide. Ever greater aggregation of misfolded amyloid-β is the early stage of Alzheimer's disease, and the more amyloid-β being generated, the faster that pathological process will progress, or at least that is the hypothesis. Today's open access paper is an example of cell culture studies being conducted to better understand the interaction between viral particles and the biochemistry of the brain. It adds a little more context to the picture, but doesn't address the conflicting epidemiological evidence.
Alzheimer's disease, a neurodegenerative memory disease, primarily results from the formation of amyloid plaques (Aβ) that gradually inhibit neuron communications. The entire mechanism of Aβ production remains unclear to date, and it is of particular interest among scientists to find out the exact mechanism that leads to amyloid precursor protein (APP) cleavage through the amyloidogenic pathway so that effective treatments can be developed.
Our hypothesis states that HSV-1 infection induces APP endocytosis, increases APP cleavage by β-secretase, and raises Aβ levels inside a cell. The Aβ peptides will then exit the cell via exocytosis to form beta-amyloid plaques. Two sets of experiments with the use of human neuroglioma cell lines are proposed to fully investigate the validity of the hypothesis. All of the experiments involve immunoblotting of Aβ using an anti-Aβ antibody, and the results would be analyzed with the assistance of an image analyzer. A significant amount of Aβ would be expected to be present in the cytoplasm of cells with herpes simplex virus (HSV-1) applied, as APP endocytosis would be induced by HSV-1, which leads to higher Aβ levels inside the cell.
Overall, we expect a high level of Aβ peptide concentration intracellularly after the introduction of HSV-1 to neuroglioma cell line. However, after the introduction of chloroquine to inhibit endocytosis, the intracellular Aβ concentration would be expected to remain normal even under HSV-1 infection. We also expect a high intracellular but low extracellular Aβ concentration for cell lines introduced with tetanus neurotoxin (TeNT) to inhibit exocytosis as the Aβ peptides are forced to accumulate in the cytoplasm. Lastly, we would expect to observe a high extracellular but low intracellular Aβ concentration for cell lines without TeNT introduction as the Aβ peptides are able to exit cells via exocytosis and aggregate extracellularly.
If all experimental data match the expected results, it can be concluded that herpesvirus infection induces Aβ peptide production in the brain due to an increase in APP endocytosis and that the peptides exit cells via exocytosis to induce the development of Alzheimer's disease.