3
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

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

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Most cited references42

          • Record: found
          • Abstract: found
          • Article: not found

          Intracellular amyloid-beta in Alzheimer's disease.

          The primal role that the amyloid-beta (Abeta) peptide has in the development of Alzheimer's disease is now almost universally accepted. It is also well recognized that Abeta exists in multiple assembly states, which have different physiological or pathophysiological effects. Although the classical view is that Abeta is deposited extracellularly, emerging evidence from transgenic mice and human patients indicates that this peptide can also accumulate intraneuronally, which may contribute to disease progression.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus

            Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer’s disease (AD) although definitive evidence has not been presented. Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration is also difficult to resolve. We constructed multiscale networks of the late onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human postmortem tissue. We observed increased human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. We observed regulatory relationships linking viral abundance and modulators of APP metabolism, including induction of APBB2 , APPBP2 , BIN1 , BACE1 , CLU , PICALM , and PSEN1 by HHV-6A. This study elucidates networks linking molecular, clinical, and neuropathological features with viral activity and is consistent with viral activity constituting a general feature of AD. Readhead et al. construct multiscale networks of the late onset Alzheimer’s disease (AD) associated virome, and observe pathogenic regulation of molecular, clinical and neuropathological networks by several common viruses, particularly human herpesvirus 6A and human herpesvirus 7.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection

              Amyloid-β peptide (Aβ) fibrilization and deposition as β-amyloid are hallmarks of Alzheimer's disease (AD) pathology. We recently reported Aβ is an innate immune protein that protects against fungal and bacterial infections. Fibrilization pathways mediate Aβ antimicrobial activities. Thus, infection can seed and dramatically accelerate β-amyloid deposition. Here, we show Aβ oligomers bind herpesvirus surface glycoproteins, accelerating β-amyloid deposition and leading to protective viral entrapment activity in 5XFAD mouse and 3D human neural cell culture infection models against neurotropic herpes simplex virus 1 (HSV1) and human herpesvirus 6A and B. Herpesviridae are linked to AD, but it has been unclear how viruses may induce β-amyloidosis in brain. These data support the notion that Aβ might play a protective role in CNS innate immunity, and suggest an AD etiological mechanism in which herpesviridae infection may directly promote Aβ amyloidosis.
                Bookmark

                Author and article information

                Contributors
                (View ORCID Profile)
                Journal
                The Journal of Infectious Diseases
                Oxford University Press (OUP)
                0022-1899
                1537-6613
                April 01 2020
                March 16 2020
                October 29 2019
                April 01 2020
                March 16 2020
                October 29 2019
                : 221
                : 7
                : 1088-1097
                Affiliations
                [1 ]Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA
                [2 ]Rocky Mountain Alzheimer’s Disease Center, University of Colorado School of Medicine, Aurora, Colorado, USA
                [3 ]Linda Crnic Institute for Down Syndrome Research, University of Colorado School of Medicine, Aurora, Colorado, USA
                [4 ]Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA
                [5 ]Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
                [6 ]Department of Ophthalmology, University of Colorado School of Medicine, Aurora, Colorado, USA
                Article
                10.1093/infdis/jiz560
                31665341
                206b5b3b-cdd6-4a07-8fdd-c50122eaa121
                © 2019

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

                History

                Comments

                Comment on this article