Acute zoster plasma contains elevated amyloid, correlating with Aβ42 and amylin levels, and is amyloidogenic

Bubak, Andrew N.; Beseler, Cheryl L.; Como, Christina N.; Tyring, Stephen K.; Haley, Christopher; Mescher, Teresa; Hassell, James E.; Cohrs, Randall J.; Potter, Huntington; Nagel, Maria A.

doi:10.1007/s13365-020-00830-7

Cited by 10 publications

(10 citation statements)

References 24 publications

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“…Intracranial VZV vasculopathy, due to productive VZV infection of cerebral arteries, is characterized by persistent inflammation that damages the vascular wall, leading to stroke, aneurysm, and other cerebrovascular abnormalities. Mechanisms of persistent inflammation are not fully characterized, but recent studies show that VZV infection in vitro and in vivo can increase intracellular and extracellular amyloid [7][8][9] ; if amyloid is not cleared efficiently, because of host or environmental factors (i.e., age-related decreases in glymphatic clearance or MMPs that catabolize amyloid) or ongoing virus replication, amyloid deposits can persist in tissue and serve as a nidus for ongoing inflammation and cytotoxicity. Herein, we examined VZV-infected HBVAFs, which are among the first cerebrovascular cells infected following VZV reactivation and spread to cerebral arteries.…”

Section: Discussionmentioning

confidence: 99%

“…The first study found that compared with 10 control plasma, 14 acute zoster plasma had significantly elevated amyloid along with elevated Aβ42 and amylin levels; zoster plasma increased amyloid aggregation with addition of exogenous Aβ42 or amylin. 8 The second study of 16 patients with VZV vasculopathy and 36 stroke controls found that VZV vasculopathy CSF had significantly increased amyloid along with increased amylin and anti-VZV antibody levels; Aβ40 was reduced and Aβ42 unchanged. 9 In the same report, primary human perineurial cells that surround nerve fibers innervating adventitia were also mock and VZV infected and found to have intracellular amylin, Aβ42, and amyloid, similar to our VZV-infected HBVAFs.…”

Section: Discussionmentioning

confidence: 99%

“…To extend the in vitro and in vivo studies that suggest a causal role for VZV in amyloid production and accumulation, [7][8][9] the VZV-infected HBVAFs transcriptional profiles were interrogated and revealed signatures relevant to amyloidassociated diseases. Significant enrichment in pathways, such as diabetes mellitus, amyloidosis, dementia, tauopathy, and Alzheimer disease, was observed (Figure 4A; list of observed DEGs in each pathway shown in eTable 3, links.lww.com/NXI/ A646).…”

Section: Vzv-infected Hbvafs Show Both Transcriptional and Protein Si...mentioning

confidence: 99%

“…7 Compared with control plasma, plasma from patients with acute zoster contains elevated amyloid along with elevated Aβ42 and amylin levels and is also amyloid promoting. 8 Similarly, compared with stroke controls, CSF from patients with VZV vasculopathy contains elevated amyloid, along with elevated amylin and anti-VZV antibody levels; Aβ40 was reduced and Aβ42 unchanged. 9 Finally, an observational study of frontal lobes from 2 cases of cerebral amyloid angiopathy (CAA) revealed VZV antigen and DNA colocalizing with Aβ in some of the affected arteries, suggesting that VZV vasculopathy may contribute to CAA pathogenesis through induction of amyloid.…”

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confidence: 98%

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Targeted RNA Sequencing of VZV-Infected Brain Vascular Adventitial Fibroblasts Indicates That Amyloid May Be Involved in VZV Vasculopathy

Bubak

Como

Hassell

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesCompared with stroke controls, patients with varicella zoster virus (VZV) vasculopathy have increased amyloid in CSF, along with increased amylin (islet amyloid polypeptide [IAPP]) and anti-VZV antibodies. Thus, we examined the gene expression profiles of VZV-infected primary human brain vascular adventitial fibroblasts (HBVAFs), one of the initial arterial cells infected in VZV vasculopathy, to determine whether they are a potential source of amyloid that can disrupt vasculature and potentiate inflammation.MethodsMock- and VZV-infected quiescent HBVAFs were harvested at 3 days postinfection. Targeted RNA sequencing of the whole-human transcriptome (BioSpyder Technologies, TempO-Seq) was conducted followed by gene set enrichment and pathway analysis. Selected pathways unique to VZV-infected cells were confirmed by enzyme-linked immunoassays, migration assays, and immunofluorescence analysis (IFA) that included antibodies against amylin and amyloid-beta, as well as amyloid staining by Thioflavin-T.ResultsCompared with mock, VZV-infected HBVAFs had significantly enriched gene expression pathways involved in vascular remodeling and vascular diseases; confirmatory studies showed secretion of matrix metalloproteinase-3 and -10, as well increased migration of infected cells and uninfected cells when exposed to conditioned media from VZV-infected cells. In addition, significantly enriched pathways involved in amyloid-associated diseases (diabetes mellitus, amyloidosis, and Alzheimer disease), tauopathy, and progressive neurologic disorder were identified; predicted upstream regulators included amyloid precursor protein, apolipoprotein E, microtubule-associated protein tau, presenilin 1, and IAPP. Confirmatory IFA showed that VZV-infected HBVAFs contained amyloidogenic peptides (amyloid-beta and amylin) and intracellular amyloid.DiscussionGene expression profiles and pathway enrichment analysis of VZV-infected HBVAFs, as well as phenotypic studies, reveal features of pathologic vascular remodeling (e.g., increased cell migration and changes in the extracellular matrix) that can contribute to cerebrovascular disease. Furthermore, the discovery of amyloid-associated transcriptional pathways and intracellular amyloid deposition in HBVAFs raise the possibility that VZV vasculopathy is an amyloid disease. Amyloid deposition may contribute to cell death and loss of vascular wall integrity, as well as potentiate chronic inflammation in VZV vasculopathy, with disease severity and recurrence determined by the host's ability to clear virus infection and amyloid deposition and by the coexistence of other amyloid-associated diseases (i.e., Alzheimer disease and diabetes mellitus).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Vzv-infected Hbvafs Show Both Transcriptional and Protein Si...mentioning

confidence: 99%

mentioning

confidence: 98%

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Targeted RNA Sequencing of VZV-Infected Brain Vascular Adventitial Fibroblasts Indicates That Amyloid May Be Involved in VZV Vasculopathy

Bubak

Como

Hassell

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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“…In a study aiming to investigate any links between shingles and three amyloid-associated diseases of ageing including AD, Bubak et al 6 found that herpes zoster (HZ) plasma has significantly higher levels of beta-amyloid and amylin than have controls, and that addition of exogenous beta-amyloid or amylin causes increases amyloid aggregation. The authors concluded that shingles might accelerate progression of these diseases via aggregation of beta-amyloid.…”

Section: Open Accessmentioning

confidence: 99%

Shingles, Zostavax vaccination and risk of developing dementia: a nested case–control study—results from the UK Biobank cohort

et al. 2021

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ObjectivesTo investigate the association between shingles and dementia, and between Zostavax vaccination and dementia.DesignNested case–control study.SettingsData were drawn from the UK Biobank cohort study with a total of 228 223 participants with Hospital Episodes Statistics and primary care linkage health records.ParticipantsThe analyses included 2378 incident dementia cases and 225 845 controls. Inclusion criteria for incident cases were a dementia diagnosis 3 years or more after the first assessment date derived from all sources including International Classification of Diseases (ICD)-10, ICD-9, self-report and primary care linkage records. Subjects with no dementia code from all sources were coded as controls. Both shingles and Zostavax vaccination were investigated for their association with dementia risk.ResultsThere was a small but non-significant increase in the risk of dementia in subjects with shingles diagnosed 3 years or more prior to dementia diagnosis (OR: 1.088 with 95% CI: 0.978 to 1.211). In those subjects who had had Zostavax vaccination, the risk of dementia significantly decreased (OR: 0.808 with 95% CI: 0.657 to 0.993).ConclusionA history of shingles was not associated with an increased risk of dementia. In subjects who were eligible for the immunisation and vaccinated with Zostavax, we saw reduced risk of developing dementia.

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Risk of dementia following herpes zoster infection among patients undertreatment versus those not: A systematic review and meta‐analysis

Thapa,

Shah,

Bhattarai

et al. 2024

Health Science Reports

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Background and AimsAccording to the previous studies, herpes zoster (HZ) has been associated with cognitive function and dementia. There is a hypothesis claiming that dementia risk may be reduced by receiving the antiviral treatment for HZ. The purpose of this systematic review and meta‐analysis was to shed light on the association between dementia and HZ in individuals receiving and not receiving antiviral medications.MethodsStudies investigating the association between HZ and dementia were identified through a systematic search in PubMed/MEDLINE, Scopus, Embase, Google Scholar, and Cochrane Library databases from January, 2000 to April, 2022. Data on the risk of dementia in HZ‐infected patients under and not under antiviral treatment were extracted. The meta‐analysis was conducted using a random‐effects model. The modified ROBIN‐I tool was used to evaluate the risk of bias assessment. By utilizing the funnel plots, publication bias was investigated.ResultsSix cohort studies on 538,531 patients were included. The overall risk of bias assessment was moderate. According to evidence‐based cohort studies, there was a significant direct association between HZ and risk of dementia in patients with HZ, who did not receive antiviral treatments (hazard ratio [HR]: 1.15, 95% confidence interval [CI]: 1.03 to 1.28, p = 0.01). On the other hand, there was an inverse relationship between HZ and risk of dementia among patients with HZ, who received antiviral treatments (HR: 0.68, 95% CI: 0.59 to 0.77, p < 0.001).ConclusionsThis study demonstrated that antiviral therapies may significantly lower the risk of dementia in patients with HZ. This study also confirmed that patients with HZ, without receiving antiviral therapies, may have an increased risk of developing dementia. Further longitudinal research is warranted in this area.

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Acute zoster plasma contains elevated amyloid, correlating with Aβ42 and amylin levels, and is amyloidogenic

Cited by 10 publications

References 24 publications

Targeted RNA Sequencing of VZV-Infected Brain Vascular Adventitial Fibroblasts Indicates That Amyloid May Be Involved in VZV Vasculopathy

Targeted RNA Sequencing of VZV-Infected Brain Vascular Adventitial Fibroblasts Indicates That Amyloid May Be Involved in VZV Vasculopathy

Shingles, Zostavax vaccination and risk of developing dementia: a nested case–control study—results from the UK Biobank cohort

Risk of dementia following herpes zoster infection among patients undertreatment versus those not: A systematic review and meta‐analysis

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