Varicella-Zoster Virus Infection of Primary Human Spinal Astrocytes Produces Intracellular Amylin, Amyloid-β, and an Amyloidogenic Extracellular Environment

Abstract

Background Herpes zoster is linked to amyloid-associated diseases, including dementia, macular degeneration, and diabetes mellitus, in epidemiological studies. Thus, we examined whether varicella-zoster virus (VZV)-infected cells produce amyloid. Methods Production of intracellular amyloidogenic proteins (amylin, amyloid precursor protein [APP], and amyloid-β [Aβ]) and amyloid, as well as extracellular amylin, Aβ, and amyloid, was compared between mock- and VZV-infected quiescent primary human spinal astrocytes (qHA-sps). The ability of supernatant from infected cells to induce amylin or Aβ42 aggregation was quantitated. Finally, the amyloidogenic activity of viral peptides was examined. Results VZV-infected qHA-sps, but not mock-infected qHA-sps, contained intracellular amylin, APP, and/or Aβ, and amyloid. No differences in extracellular amylin, Aβ40, or Aβ42 were detected, yet only supernatant from VZV-infected cells induced amylin aggregation and, to a lesser extent, Aβ42 aggregation into amyloid fibrils. VZV glycoprotein B (gB) peptides assembled into fibrils and catalyzed amylin and Aβ42 aggregation. Conclusions VZV-infected qHA-sps produced intracellular amyloid and their extracellular environment promoted aggregation of cellular peptides into amyloid fibrils that may be due, in part, to VZV gB peptides. These findings suggest that together with host and other environmental factors, VZV infection may increase the toxic amyloid burden and contribute to amyloid-associated disease progression.

Cerebral Fructose Metabolism as a Potential Mechanism Driving Alzheimer’s Disease

“…The pathogenesis of Alzheimer's disease is complex and involves multiple genetic and environmental factors, and our purpose is to present a new hypothesis that links mitochondrial dysfunction, cerebral energetics, cerebral insulin resistance, and diet that might encourage further research. We do not negate the role of other factors, such as varicella-zoster viral infection, that may induce similar pathways (Bubak et al, 2019). We also recognize that the role of dietary fats is complex and that the balance of omega3 to omega6 may also be important, and how this relates to fructose metabolism requires further study (Simopoulos, 2013).…”

Herpes Zoster Does Not Increase the Risk of Neurodegenerative Dementia: A Case-Control Study

“…27,28 In a spinal astrocyte cell culture study, VZV-infected cells led to intracellular amyloid accumulation, but whether dementia occurs due to amyloid accumulation induced by HZI remains unclear. 29 Vascular dementia accounts for up to 20% of all cases of dementia and is caused by multiple cerebral infarctions from cerebrovascular or cardiovascular problems, including DM, hypertension, stroke and metabolic syndrome. 30 VZV invades the spinal cord or cerebral arteries directly or after reactivation.…”

Amyloid precursor protein causes fusion of promyelocytic leukemia nuclear bodies in human hippocampal areas with high plaque load

“…it was shown that the peptide inhibits the replication of seasonal and pandemic strains of H3N2 and H1N1 influenza A virus (IAV) in vitro 56 . Moreover, VZV-infection of primary human spinal astrocytes induce an extracellular amyloidogenic environment 57 . Clinical studies reveal a deposition of amyloid-ß plaques in the brains of HIV-infected individuals 58 and infections by HSV cause not only elevated ß-amyloid production but also phosphorylation of Tau 59,60 .…”