scholarly journals Multigenomics Reveals the Causal Effect of Herpes Simplex Virus in Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study

2022 ◽  
Vol 12 ◽  
Author(s):  
Yuwei Zhang ◽  
Jiaojiao Qu ◽  
Li Luo ◽  
Zhongshun Xu ◽  
Xiao Zou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
Analysis Model ◽  
Simplex Virus ◽  
Hsv 1

In recent years, the herpes virus infectious hypothesis for Alzheimer’s disease (AD) has gained support from an increasing number of researchers. Herpes simplex virus (HSV) is a potential risk factor associated with AD. This study assessed whether HSV has a causal relationship with AD using a two-sample Mendelian randomization analysis model. Six single-nucleotide polymorphisms (SNPs) associated with HSV-1 and thirteen SNPs associated with HSV-2 were used as instrumental variables in the MR analysis. We estimated MR values of relevance between exposure and the risk of AD using inverse-variance weighted (IVW) method, MR-Egger regression (Egger), and weighted median estimator (WME). To make the conclusion more robust and reliable, sensitivity analyses and RadialMR were performed to evaluate the pleiotropy and heterogeneity. We found that anti-HSV-1 IgG measurements were not associated with risk of AD (OR, 0.96; 95% CI, 0.79–1.18; p = 0.736), and the same was true for HSV-2 (OR, 1.03; 95% CI, 0.94–1.12; p = 0.533). The findings indicated that any HSV infection does not appear to be a genetically valid target of intervention in AD.

Independent and Correlated Role of Apolipoprotein E ɛ4 Genotype and Herpes Simplex Virus Type 1 in Alzheimer’s Disease

2020 ◽  
Vol 77 (1) ◽  
pp. 15-31
Author(s):  
Li-Na Zhang ◽  
Meng-Jie Li ◽  
Ying-Hui Shang ◽  
Fan-Fan Zhao ◽  
Han-Chang Huang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Apolipoprotein E ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Simplex Virus ◽  
Hsv 1

The ɛ4 allele of the Apolipoprotein E (APOE) gene in individuals infected by Herpes simplex virus type 1 (HSV-1) has been demonstrated to be a risk factor in Alzheimer’s disease (AD). APOE-ɛ4 reduces the levels of neuronal cholesterol, interferes with the transportation of cholesterol, impairs repair of synapses, decreases the clearance of neurotoxic peptide amyloid-β (Aβ), and promotes the deposition of amyloid plaque, and eventually may cause development of AD. HSV-1 enters host cells and can infect the olfactory system, trigeminal ganglia, entorhinal cortex, and hippocampus, and may cause AD-like pathological changes. The lifecycle of HSV-1 goes through a long latent phase. HSV-1 induces neurotropic cytokine expression with pro-inflammatory action and inhibits antiviral cytokine production in AD. It should be noted that interferons display antiviral activity in HSV-1-infected AD patients. Reactivated HSV-1 is associated with infectious burden in cognitive decline and AD. Finally, HSV-1 DNA has been confirmed as present in human brains and is associated with APOE ɛ4 in AD. HSV-1 and APOE ɛ4 increase the risk of AD and relate to abnormal autophagy, higher concentrations of HSV-1 DNA in AD, and formation of Aβ plaques and neurofibrillary tangles.

scholarly journals Multiple Herpes Simplex Virus-1 (HSV-1) Reactivations Induce Protein Oxidative Damage in Mouse Brain: Novel Mechanisms for Alzheimer’s Disease Progression

2020 ◽  
Vol 8 (7) ◽  
pp. 972 ◽  
Author(s):  
Virginia Protto ◽  
Antonella Tramutola ◽  
Marco Fabiani ◽  
Maria Elena Marcocci ◽  
Giorgia Napoletani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Oxidative Damage ◽  
Mouse Brain ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

Compelling evidence supports the role of oxidative stress in Alzheimer’s disease (AD) pathophysiology. Interestingly, Herpes simplex virus-1 (HSV-1), a neurotropic virus that establishes a lifelong latent infection in the trigeminal ganglion followed by periodic reactivations, has been reportedly linked both to AD and to oxidative stress conditions. Herein, we analyzed, through biochemical and redox proteomic approaches, the mouse model of recurrent HSV-1 infection we previously set up, to investigate whether multiple virus reactivations induced oxidative stress in the mouse brain and affected protein function and related intracellular pathways. Following multiple HSV-1 reactivations, we found in mouse brains increased levels of oxidative stress hallmarks, including 4-hydroxynonenal (HNE), and 13 HNE-modified proteins whose levels were found significantly altered in the cortex of HSV-1-infected mice compared to controls. We focused on two proteins previously linked to AD pathogenesis, i.e., glucose-regulated protein 78 (GRP78) and collapsin response-mediated protein 2 (CRMP2), which are involved in the unfolded protein response (UPR) and in microtubule stabilization, respectively. We found that recurrent HSV-1 infection disables GRP78 function and activates the UPR, whereas it prevents CRMP2 function in mouse brains. Overall, these data suggest that repeated HSV-1 reactivation into the brain may contribute to neurodegeneration also through oxidative damage.

scholarly journals Persistent Infection with Herpes Simplex Virus 1 and Alzheimer’s Disease—A Call to Study How Variability in Both Virus and Host may Impact Disease

Viruses ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 966 ◽  
Author(s):  
Colleen A. Mangold ◽  
Moriah L. Szpara
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Future Research ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

Increasing attention has focused on the contributions of persistent microbial infections with the manifestation of disease later in life, including neurodegenerative conditions such as Alzheimer’s disease (AD). Current data has shown the presence of herpes simplex virus 1 (HSV-1) in regions of the brain that are impacted by AD in elderly individuals. Additionally, neuronal infection with HSV-1 triggers the accumulation of amyloid beta deposits and hyperphosphorylated tau, and results in oxidative stress and synaptic dysfunction. All of these factors are implicated in the development of AD. These data highlight the fact that persistent viral infection is likely a contributing factor, rather than a sole cause of disease. Details of the correlations between HSV-1 infection and AD development are still just beginning to emerge. Future research should investigate the relative impacts of virus strain- and host-specific factors on the induction of neurodegenerative processes over time, using models such as infected neurons in vitro, and animal models in vivo, to begin to understand their relationship with cognitive dysfunction.

scholarly journals The Hippocampal Vulnerability to Herpes Simplex Virus Type I Infection: Relevance to Alzheimer’s Disease and Memory Impairment

2021 ◽  
Vol 15 ◽  
Author(s):  
Shin Jie Yong ◽  
Min Hooi Yong ◽  
Seong Lin Teoh ◽  
Tomoko Soga ◽  
Ishwar Parhar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Type I ◽  
Brain Disorders ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus type 1 (HSV-1) as a possible infectious etiology in Alzheimer’s disease (AD) has been proposed since the 1980s. The accumulating research thus far continues to support the association and a possible causal role of HSV-1 in the development of AD. HSV-1 has been shown to induce neuropathological and behavioral changes of AD, such as amyloid-beta accumulation, tau hyperphosphorylation, as well as memory and learning impairments in experimental settings. However, a neuroanatomical standpoint of HSV-1 tropism in the brain has not been emphasized in detail. In this review, we propose that the hippocampal vulnerability to HSV-1 infection plays a part in the development of AD and amnestic mild cognitive impairment (aMCI). Henceforth, this review draws on human studies to bridge HSV-1 to hippocampal-related brain disorders, namely AD and aMCI/MCI. Next, experimental models and clinical observations supporting the neurotropism or predilection of HSV-1 to infect the hippocampus are examined. Following this, factors and mechanisms predisposing the hippocampus to HSV-1 infection are discussed. In brief, the hippocampus has high levels of viral cellular receptors, neural stem or progenitor cells (NSCs/NPCs), glucocorticoid receptors (GRs) and amyloid precursor protein (APP) that support HSV-1 infectivity, as well as inadequate antiviral immunity against HSV-1. Currently, the established diseases HSV-1 causes are mucocutaneous lesions and encephalitis; however, this review revises that HSV-1 may also induce and/or contribute to hippocampal-related brain disorders, especially AD and aMCI/MCI.

scholarly journals Alzheimer’s disease-associated β-Amyloid does not protect against Herpes Simplex Virus 1 brain infection

2021 ◽  
Author(s):  
Olga Bocharova ◽  
Kara Molesworth ◽  
Narayan P. Pandit ◽  
Ilia V. Baskakov
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Late Onset ◽  
Protective Role ◽  
Herpes Simplex Virus 1 ◽  
Brain Infection ◽  
Simplex Virus ◽  
Hsv 1

AbstractAlzheimer’s disease (AD) is devastating fatal neurodegenerative disease. An alternative to the amyloid cascade hypothesis is the hypothesis that a viral infection is key to the etiology of late-onset AD, with amyloid Aβ peptides playing a protective role. Contrary to previous work, in the current study the 5XFAD genotype failed to protect mice against infection with two strains of herpes simplex virus 1 (HSV-1), 17syn+ and McKrae. Moreover, the region- or cell-specific tropisms of HSV-1 were not affected by the 5XFAD genotype, arguing that host-pathogen interactions were not altered. In aged 5XFAD mice with abundant Aβ plaques, only small, statistically non-significant protection against acute HSV-1 infection was observed, yet no colocalization between HSV-1 and Aβ plaques was found. While the current study questions the antiviral role of APP or Aβ, it neither supports nor refutes the viral etiology hypothesis of late-onset AD.

scholarly journals Amyloid-β and p-Tau Anti-Threat Response to Herpes Simplex Virus 1 Infection in Primary Adult Murine Hippocampal Neurons

2020 ◽  
Vol 94 (9) ◽  
Author(s):  
Rebecca D. Powell-Doherty ◽  
Amber R. N. Abbott ◽  
Laura A. Nelson ◽  
Andrea S. Bertke
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Hippocampal Neurons ◽  
The United States ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Tau Expression ◽  
Hsv 1

ABSTRACT Alzheimer’s Disease (AD) is the sixth leading cause of death in the United States. Recent studies have established a potential link between herpes simplex virus 1 (HSV-1) infection and the development of AD. HSV-1 DNA has been detected in AD amyloid plaques in human brains, and treatment with the antiviral acyclovir (ACV) was reported to block the accumulation of the AD-associated proteins beta-amyloid (Aβ) and hyper-phosphorylated tau (p-tau) in Vero and glioblastoma cells. Our goal was to determine whether the accumulation of AD-related proteins is attributable to acute and/or latent HSV-1 infection in mature hippocampal neurons, a region of the brain severely impacted by AD. Primary adult murine hippocampal neuronal cultures infected with HSV-1, with or without antivirals, were assessed for Aβ and p-tau expression over 7 days postinfection. P-tau expression was transiently elevated in HSV-1-infected neurons, as well as in the presence of antivirals alone. Infected neurons, as well as uninfected neurons treated with antivirals, had a greater accumulation of Aβ42 than uninfected untreated neurons. Furthermore, Aβ42 colocalized with HSV-1 latency-associated transcript (LAT) expression. These studies suggest that p-tau potentially acts as an acute response to any perceived danger-associated molecular pattern (DAMP) in primary adult hippocampal neurons, while Aβ aggregation is a long-term response to persistent threats, including HSV-1 infection. IMPORTANCE Growing evidence supports a link between HSV-1 infection and Alzheimer’s disease (AD). Although AD is clearly a complex multifactorial disorder, an infectious disease etiology provides alternative therapy opportunities for this devastating disease. Understanding the impact that HSV-1 has on mature neurons and the proteins most strongly associated with AD pathology may identify specific mechanisms that could be manipulated to prevent progression of neurodegeneration and dementia.

scholarly journals Herpes simplex virus, early neuroimaging markers and incidence of Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Morgane Linard ◽  
Marion Baillet ◽  
Luc Letenneur ◽  
Isabelle Garrigue ◽  
Gwenaëlle Catheline ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Diffusion Tensor ◽  
Hippocampal Volume ◽  
Potential Interaction ◽  
Increased Risk ◽  
Simplex Virus ◽  
Igg Level

AbstractWhile previous studies suggest the implication of herpes simplex virus (HSV) in the onset of Alzheimer’s disease (AD), no study has investigated its association with early neuroimaging markers of AD. In the Three-City and the AMI cohorts, the associations between HSV infection and (i) hippocampal volume (n = 349), (ii) white matter alterations in the parahippocampal cingulum and fornix using diffusion tensor imaging (n = 260), and (iii) incidence of AD (n = 1599) were assessed according to APOE4 status. Regardless of APOE4 status, infected subjects presented (i) significantly more microstructural alterations of the parahippocampal cingulum and fornix, (ii) lower hippocampal volumes only when their anti-HSV IgG level was in the highest tercile—reflecting possibly more frequent reactivations of the virus (p = 0.03 for subjects with a high anti-HSV IgG level while there was no association for all infected subjects, p = 0.19), and (iii) had no increased risk of developing AD. Nevertheless, among APOE4 carriers, infected subjects presented lower hippocampal volumes, although not significant (p = 0.09), and a two or three times higher risk of developing AD (adjusted Hazard ratio (aHR) = 2.72 [1.07–6.91] p = 0.04 for infected subjects and aHR = 3.87 [1.45–10.28] p = 0.007 for infected subjects with an anti-HSV IgG level in the highest tercile) while no association was found among APOE4 noncarriers. Our findings support an association between HSV infection and AD and a potential interaction between HSV status and APOE4. This reinforces the need to further investigate the infectious hypothesis of AD, especially the associated susceptibility factors and the possibility of preventive treatments.

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