Herpes simplex virus alters Alzheimer's disease biomarkers ‐ A hypothesis paper

Goldhardt, Oliver; Freiberger, Robert H.; Dreyer, Tobias; Wilner, Luisa; Yakushev, Igor; Ortner, Marion; Förstl, Hans; Diehl‐Schmid, Janine; Milz, Esther; Priller, Josef; Ramı́rez, Alfredo; Magdolen, Viktor; Thaler, Markus; Grimmer, Timo

doi:10.1002/alz.12834

Cited by 9 publications

(6 citation statements)

References 71 publications

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“…Using cell culture and animal models, we explore how human herpes simplex virus 1 (HSV1) causes amyloid-β (Aβ) buildup and neurofibrillary tangles of hyperphosphorylated tau (pTau) in AD. A seems to have a virostatic effect ( 70 ).…”

Section: Environmental Risk Factorsmentioning

confidence: 99%

Alzheimer’s disease: the role of extrinsic factors in its development, an investigation of the environmental enigma

Suresh,

Singh S,

Rushendran

et al. 2023

Front. Neurol.

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In the realm of Alzheimer’s disease, the most prevalent form of dementia, the impact of environmental factors has ignited intense curiosity due to its substantial burden on global health. Recent investigations have unveiled these environmental factors as key contributors, shedding new light on their profound influence. Notably, emerging evidence highlights the detrimental role of various environmental contaminants in the incidence and progression of Alzheimer’s disease. These contaminants encompass a broad spectrum, including air pollutants laden with ozone, neurotoxic metals like lead, aluminum, manganese, and cadmium, pesticides with their insidious effects, and the ubiquitous presence of plastics and microplastics. By meticulously delving into the intricate web connecting environmental pollutants and this devastating neurological disorder, this comprehensive chapter takes a deep dive into their involvement as significant risk factors for Alzheimer’s disease. Furthermore, it explores the underlying molecular mechanisms through which these contaminants exert their influence, aiming to unravel the complex interactions that drive the pathogenesis of the disease. Additionally, this chapter proposes potential strategies to mitigate the detrimental effects of these environmental contaminants on brain health, with the ultimate goal of restoring and preserving typical cognitive function. Through this comprehensive exploration, we aim to enhance our understanding of the multifaceted relationship between neurotoxins and Alzheimer’s disease, providing a solid foundation for developing innovative in-vivo models and advancing our knowledge of the intricate pathological processes underlying this debilitating condition.

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Section: Environmental Risk Factorsmentioning

confidence: 99%

Alzheimer’s disease: the role of extrinsic factors in its development, an investigation of the environmental enigma

Suresh,

Singh S,

Rushendran

et al. 2023

Front. Neurol.

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“…Some studies also suggested that the aggregation of pTau may be induced by infections, among other factors ( Lee et al, 2022 ; Sathler et al, 2022 ; Shen et al, 2022 ; Tang et al, 2022 ). The involvement of infections in AD is an emerging field of AD research, and the literature on the factors that may influence both vulnerability to infections and neurodegeneration is increasing ( Yashin et al, 2018 ; Yong et al, 2021 ; Cairns, Itzhaki and Kaplan, 2022 ; Mancuso et al, 2022 ; Nuovo et al, 2022 ; Piekut et al, 2022 ; Sathler et al, 2022 ; Tang et al, 2022 ; Goldhardt et al, 2023 ; Ukraintseva et al, 2023 ; Popov et al, 2024 ). Nectin-2 (Nectin cell adhesion molecule 2) is a membrane component of adherens junctions that serves as an entry point for certain herpesviruses and may mediate response to the viral infection ( Ogawa et al, 2022 ; Goldhardt et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

“…The involvement of infections in AD is an emerging field of AD research, and the literature on the factors that may influence both vulnerability to infections and neurodegeneration is increasing ( Yashin et al, 2018 ; Yong et al, 2021 ; Cairns, Itzhaki and Kaplan, 2022 ; Mancuso et al, 2022 ; Nuovo et al, 2022 ; Piekut et al, 2022 ; Sathler et al, 2022 ; Tang et al, 2022 ; Goldhardt et al, 2023 ; Ukraintseva et al, 2023 ; Popov et al, 2024 ). Nectin-2 (Nectin cell adhesion molecule 2) is a membrane component of adherens junctions that serves as an entry point for certain herpesviruses and may mediate response to the viral infection ( Ogawa et al, 2022 ; Goldhardt et al, 2023 ). The single nucleotide polymorphism (SNP) rs6859 of the NECTIN2 gene was highly significantly associated with AD risk in observational human data ( Yashin et al, 2018 ; Mizutani et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

The association between rs6859 inNECTIN2gene and Alzheimer’s disease is partly mediated by pTau

Lathika Rajendrakumar,

Arbeev,

Bagley

et al. 2024

Preprint

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IntroductionEmerging evidence suggests a connection between vulnerability to infections and Alzheimer’s disease (AD). The nectin cell adhesion molecule 2(NECTIN2)gene coding for a membrane component of adherens junctions is involved in response to infection, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology. The aggregation of hyperphosphorylated tau protein (pTau) is a key pathological feature of neurodegeneration in AD, which may be induced by infections, among other factors, and potentially influenced by genes involved in both AD and vulnerability to infections, such asNECTIN2.Materials and methodsWe conducted a causal mediation analysis (CMA) on a sample of 708 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The relationship between rs6859 and Alzheimer’s disease (AD), with AD (yes/no) as the outcome and pTau-181 levels in the cerebrospinal fluid (CSF) acting as a mediator in this association, was assessed. Adjusted estimates from the probit and linear regression models were used in the CMA model, where an additive model considered an increase in dosage of the rs6859 A allele (AD risk factor).ResultsThe increase in dose of allele A of the SNP rs6859 resulted in about 0.144 increase per standard deviation (SD) of pTau-181 (95% CI: 0.041, 0.248, p<0.01). When included together in the probit model, the change in A allele dose and each standard deviation change in pTau-181 predicted 6.84% and 9.79% higher probabilities for AD, respectively. In the CMA, the proportion of the average mediated effect was 17.05% and was higher for the risk allele homozygotes (AA), at 19.40% (95% CI: 6.20%, 43.00%, p<0.01). The sensitivity analysis confirmed the evidence of a robust mediation effect.ConclusionThis study reported a new causal relationship between pTau-181 and AD. We found that the association between rs6859 in theNECTIN2gene and AD is partly mediated by pTau-181 levels in CSF. The rest of this association may be mediated by other factors. Further research, using other biomarkers, is needed to uncover the remaining mechanisms of the association between theNECTIN2gene and AD.

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“…Reactivation of latent herpes virus infection has been associated to Alzheimer’s disease (AD) even though the molecular mechanisms of this connection remains unknown (Eimer et al, 2018; Itzhaki et al, 1997; Lovheim et al, 2015; Wozniak et al, 2009). Recently, a positive association of HSV-1 antibodies to increased levels of phosphorylated tau in CSF of AD patients was demonstrated (Goldhardt et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Oxidized MIF is an Alzheimer’s Disease drug target relaying external risk factors to tau pathology

Mueller-Schiffmann

Torres

Kitaygorodskyy³

et al. 2021

Preprint

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Herpes virus infections are endemic and ubiquitous. While only rarely leading to overt encephalitis, subchronic or latent infections have been associated to a variety of conditions, including Alzheimer's disease (AD). The cellular consequences of herpes virus infection are determined by the host proteins recruited during virus replication and assembly. Identifying such virus-recruited host proteins therefore allows the interrogation fundamental cellular events leading to associated "sporadic" diseases. A host protein-targeted small molecule drug highly active against herpes simplex virus 1 (HSV-1) infection in human brain organoids and cell lines was identified to interact with macrophage migration inhibitory factor (MIF) where it acted by intercalating between MIF units within a trimer, as determined by nuclear magnetic resonance (NMR). MIF knockout cells showed a decreased viral antigen/titer ratio corroborating its role in virus assembly. From post-mortem brain homogenates of patients with Braak 6-staged AD the small molecule lead compound specifically eluted a MIF subpopulation that correlated with the oxidized conformer of MIF (oxMIF). HSV-1 led to an increase in tau phosphorylation at distinct residues, and the lead compound decreased tau phosphorylation in recombinant cell lines expressing mutant tau and in neuron-differentiated iPSCs also in the absence of HSV-1 infection. We conclude that MIF is a cellular host factor involved in HSV-1 replication and a drug target with antiviral efficacy. At the same time, MIF also plays a role in tau phosphorylation and is enriched in an oxidized conformation in brains of AD patients. MIF thus presents as a molecular link connecting HSV-1 infection and cellular pathology characteristic of neurodegenerative diseases involving aberrant tau phosphorylation.

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Herpes simplex virus alters Alzheimer's disease biomarkers ‐ A hypothesis paper

Cited by 9 publications

References 71 publications

Alzheimer’s disease: the role of extrinsic factors in its development, an investigation of the environmental enigma

Alzheimer’s disease: the role of extrinsic factors in its development, an investigation of the environmental enigma

The association between rs6859 inNECTIN2gene and Alzheimer’s disease is partly mediated by pTau

Oxidized MIF is an Alzheimer’s Disease drug target relaying external risk factors to tau pathology

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