P4-059: Induction of amyloid processing in astrocytes and neuronal cells coinfected with herpes simplex virus 1 and Chlamydophila (Chlamydia) pneumoniae : Linkage of an infectious process to Alzheimer's disease

Abstract IntroductionHerpes Simplex Virus 1 (HSV1) is a neuroinvasive virus capable of entering the brain which makes it a candidate pathogen for increasing risk of dementia. Previous studies are inconsistent in their findings regarding the link between HSV1 and dementia, therefore, we investigated how HSV1 relates to cognitive decline and dementia risk using data from a population-based study. MethodsWe measured HSV1 immunoglobulin (IgG) antibodies in serum collected between 2002 and 2005 from participants of the Rotterdam Study. We used linear regression to determine HSV1 in relation to change in cognitive performance during 2 consecutive examination rounds on average 6,5 years apart. Next, we determined the association of HSV1 with risk of dementia (until 2016) using a Cox regression model. We repeated analyses for Alzheimer’s disease. All models were adjusted for age, sex, cardiovascular risk factors, and apolipoprotein E genotype. Results Of 1,915 non-demented participants (mean age 71.3 years, 56.7% women), with an average follow-up time of 9.1 years, 244 participants developed dementia (of whom 203 Alzheimer’s disease). HSV1 seropositivity was associated with decline in global cognition (mean difference per standard deviation -0.16; 95% confidence interval (95%CI), -0.26; -0.07), as well as separate cognitive domains, namely memory, information processing, and executive function, but not motor function. Finally, HSV1 seropositivity was not associated with risk of dementia (adjusted hazard ratio, 1.18, 95%CI, 0.83; 1.68), similar for Alzheimer’s disease. DiscussionHSV1 is associated with cognitive decline but not with incident dementia in the general population. These data suggest HSV1 to be associated only with subtle cognitive disturbances but not with greater cognitive disorders that result in dementia.

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

Microorganisms ◽

10.3390/microorganisms8070972 ◽

2020 ◽

Vol 8 (7) ◽

pp. 972 ◽

Cited By ~ 2

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.

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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 ◽

10.3390/v11100966 ◽

2019 ◽

Vol 11 (10) ◽

pp. 966 ◽

Cited By ~ 5

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.

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Herpes simplex virus 1 and the risk of dementia: a population-based study

Scientific Reports ◽

10.1038/s41598-021-87963-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Meghan J. Murphy ◽

Lana Fani ◽

M. Kamran Ikram ◽

Mohsen Ghanbari ◽

M. Arfan Ikram

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Cognitive Decline ◽

Population Based ◽

Herpes Simplex Virus 1 ◽

Population Based Study ◽

Global Cognition ◽

Simplex Virus

AbstractHerpes simplex virus 1 (HSV1) is a neuroinvasive virus capable of entering the brain which makes it a candidate pathogen for increasing risk of dementia. Previous studies are inconsistent in their findings regarding the link between HSV1 and dementia, therefore, we investigated how HSV1 relates to cognitive decline and dementia risk using data from a population-based study. We measured HSV1 immunoglobulin (IgG) antibodies in serum collected between 2002 and 2005 from participants of the Rotterdam Study. We used linear regression to determine HSV1 in relation to change in cognitive performance during 2 consecutive examination rounds on average 6.5 years apart. Next, we determined the association of HSV1 with risk of dementia (until 2016) using a Cox regression model. We repeated analyses for Alzheimer’s disease. All models were adjusted for age, sex, cardiovascular risk factors, and apolipoprotein E genotype. Of 1915 non-demented participants (mean age 71.3 years, 56.7% women), with an average follow-up time of 9.1 years, 244 participants developed dementia (of whom 203 Alzheimer’s disease). HSV1 seropositivity was associated with decline in global cognition (mean difference of HSV1 seropositive vs seronegative per standard deviation decrease in global cognition − 0.16; 95% confidence interval (95%CI), − 0.26; − 0.07), as well as separate cognitive domains, namely memory, information processing, and executive function, but not motor function. Finally, HSV1 seropositivity was not associated with risk of dementia (adjusted hazard ratio 1.18, 95% CI 0.83; 1.68), similar for Alzheimer’s disease. HSV1 is associated with cognitive decline but not with incident dementia in the general population. These data suggest HSV1 to be associated only with subtle cognitive disturbances but not with greater cognitive disorders that result in dementia.

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

10.1101/2021.01.21.427570 ◽

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.

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