Mechanistic insights into the role of herpes simplex virus 1 in Alzheimer’s disease

Feng, Shu; Liu, Yongzhen; Zhou, Yu; Shu, Zhenfeng; Cheng, Zhuxi; Brenner, Charles; Feng, Pinghui

doi:10.3389/fnagi.2023.1245904

Cited by 13 publications

(4 citation statements)

References 162 publications

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“…Other studies also showed that inhibition of glycolysis resulted in a significant decrease in HSV propagation [30,31]. There are differing results regarding the impact of HSV infection on the TCA cycle and oxidative phosphorylation including the potential shift from the TCA cycle and oxidative phosphorylation to the pentose phosphate pathway [32]. However, it was also shown previously that the HSV-1 UL43 protein was localized to the mitochondria, and increased aerobic oxidation and oxidative phosphorylation of glucose resulted in an overall increase in ATP generation [33].…”

Section: Discussionmentioning

confidence: 99%

Carnosic Acid Inhibits Herpes Simplex Virus Replication by Suppressing Cellular ATP Synthesis

Horváth,

Molnár,

Szabó

et al. 2024

IJMS

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Acquiring resistance against antiviral drugs is a significant problem in antimicrobial therapy. In order to identify novel antiviral compounds, the antiviral activity of eight plants indigenous to the southern region of Hungary against herpes simplex virus-2 (HSV-2) was investigated. The plant extracts and the plant compound carnosic acid were tested for their effectiveness on both the extracellular and intracellular forms of HSV-2 on Vero and HeLa cells. HSV-2 replication was measured by a direct quantitative PCR (qPCR). Among the tested plant extracts, Salvia rosmarinus (S. rosmarinus) exhibited a 90.46% reduction in HSV-2 replication at the 0.47 μg/mL concentration. Carnosic acid, a major antimicrobial compound found in rosemary, also demonstrated a significant dose-dependent inhibition of both extracellular and intracellular forms of HSV-2. The 90% inhibitory concentration (IC90) of carnosic acid was between 25 and 6.25 μg/mL. Proteomics and high-resolution respirometry showed that carnosic acid suppressed key ATP synthesis pathways such as glycolysis, citrate cycle, and oxidative phosphorylation. Inhibition of oxidative phosphorylation also suppressed HSV-2 replication up to 39.94-fold. These results indicate that the antiviral action of carnosic acid includes the inhibition of ATP generation by suppressing key energy production pathways. Carnosic acid holds promise as a potential novel antiviral agent against HSV-2.

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Section: Discussionmentioning

confidence: 99%

Carnosic Acid Inhibits Herpes Simplex Virus Replication by Suppressing Cellular ATP Synthesis

Horváth,

Molnár,

Szabó

et al. 2024

IJMS

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“…HSV-1 is a ubiquitous virus that affects more than 80% of people over 65 across the globe [ 29 ]. There exists a detailed and eloquent review by Shu Feng and colleagues that really delves into the details surrounding HSV-1 in AD [ 30 ]. We decided to add to the discussion, mainly in our future directions discussion, Section 4.1.4 ., below.…”

Section: Elaboration Of Selected Viral Examples Implicated In Ad and ...mentioning

confidence: 99%

“…Currently, some studies suggest a potential association between HSV-1 and AD, but the nature of this association remains unclear. There are several recent reviews that have listed and discussed many studies on the potential importance of HSV-1 in AD development [ 30 , 49 , 50 , 51 ]. Herein, we have dawn on some well-known or well-understood examples that we hope to continue to add to this perspective on HSV-1 and the infection process.…”

Section: Elaboration Of Selected Viral Examples Implicated In Ad and ...mentioning

confidence: 99%

Viral Infections, Are They a Trigger and Risk Factor of Alzheimer’s Disease?

Rippee-Brooks,

Wu,

Dong

et al. 2024

Pathogens

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Alzheimer’s Disease (AD), a progressive and debilitating condition, is reported to be the most common type of dementia, with at least 55 million people believed to be currently affected. Many causation hypotheses of AD exist, yet the intriguing link between viral infection and its possible contribution to the known etiology of AD has become an attractive focal point of research for the field and a challenging study task. In this review, we will explore the historical perspective and milestones that led the field to investigate the viral connection to AD. Specifically, several viruses such as Herpes Simplex Virus 1 (HSV-1), Zika virus (ZIKV), and severe cute respiratory syndrome coronavirus 2 (SARS-CoV-2), along with several others mentioned, include the various viruses presently considered within the field. We delve into the strong evidence implicating these viruses in the development of AD such as the lytic replication and axonal transport of HSV-1, the various mechanisms of ZIKV neurotropism through the human protein Musashi-1 (MSI1), and the spread of SARS-CoV-2 through the transfer of the virus through the BBB endothelial cells to glial cells and then to neurons via transsynaptic transfer. We will also explore beyond these mere associations by carefully analyzing the potential mechanisms by which these viruses may contribute to AD pathology. This includes but is not limited to direct neuronal infections, the dysregulation of immune responses, and the impact on protein processing (Aβ42 and hyperphosphorylated tau). Controversies and challenges of the virus–AD relationship emerge as we tease out these potential mechanisms. Looking forward, we emphasize future directions, such as distinct questions and proposed experimentations to explore, that the field should take to tackle the remaining unanswered questions and the glaring research gaps that persist. Overall, this review aims to provide a comprehensive survey of the past, present, and future of the potential link between viral infections and their association with AD development while encouraging further discussion.

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“…Although somewhat controversial, increasing experimental and epidemiological evidence indicates that viral infections are an environmental risk factor for the development of neurodegeneration and neurological sequelae [9]. For example, neurotropic pathogens, such as human herpes virus (HHV), herpes simplex virus (HSV), hepatitis C virus (HCV), cytomegalovirus, varicella-zoster virus, and Epstein-Barr virus are associated with Alzheimer's disease (AD) neuropathology [10][11][12][13]. Although previous studies do not indicate VEEV is related to neurodegeneration, VEEV neurological sequelae share progressive characteristics of neurodegenerative disorders including cognitive, motor, or sensory deficits [4,14,15].…”

Section: Introductionmentioning

confidence: 99%

VEEV TC-83 Triggers Dysregulation of the Tryptophan–Kynurenine Pathway in the Central Nervous System That Correlates with Cognitive Impairment in Tg2576 Mice

Fongsaran,

Dineley,

Paessler

et al. 2024

Pathogens

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Neurodegenerative diseases are chronic conditions affecting the central nervous system (CNS). Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid beta in the limbic and cortical brain regions. AD is presumed to result from genetic abnormalities or environmental factors, including viral infections, which may have deleterious, long-term effects. In this study, we demonstrate that the Venezuelan equine encephalitis virus (VEEV) commonly induces neurodegeneration and long-term neurological or cognitive sequelae. Notably, the effects of VEEV infection can persistently influence gene expression in the mouse brain, suggesting a potential link between the observed neurodegenerative outcomes and long-term alterations in gene expression. Additionally, we show that alphavirus encephalitis exacerbates the neuropathological profile of AD through crosstalk between inflammatory and kynurenine pathways, generating a range of metabolites with potent effects. Using a mouse model for β-amyloidosis, Tg2576 mice, we found that cognitive deficits and brain pathology were more severe in Tg2576 mice infected with VEEV TC-83 compared to mock-infected controls. Thus, during immune activation, the kynurenine pathway plays a more active role in the VEEV TC-83-infected cells, leading to increases in the abundance of transcripts related to the kynurenine pathway of tryptophan metabolism. This pathway generates several metabolites with potent effects on neurotransmitter systems as well as on inflammation, as observed in VEEV TC-83-infected animals.

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Mechanistic insights into the role of herpes simplex virus 1 in Alzheimer’s disease

Cited by 13 publications

References 162 publications

Carnosic Acid Inhibits Herpes Simplex Virus Replication by Suppressing Cellular ATP Synthesis

Carnosic Acid Inhibits Herpes Simplex Virus Replication by Suppressing Cellular ATP Synthesis

Viral Infections, Are They a Trigger and Risk Factor of Alzheimer’s Disease?

VEEV TC-83 Triggers Dysregulation of the Tryptophan–Kynurenine Pathway in the Central Nervous System That Correlates with Cognitive Impairment in Tg2576 Mice

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