Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice

Chiara, Giovanna De; Piacentini, Roberto; Fabiani, Marco; Mastrodonato, Alessia; Marcocci, Maria Elena; Limongi, Dolores; Napoletani, Giorgia; Protto, Virginia; Coluccio, Paolo; Celestino, Ignacio; Puma, Domenica Donatella Li; Grassi, Claudio; Palamara, Anna Teresa

doi:10.1371/journal.ppat.1007617

Cited by 169 publications

(217 citation statements)

References 69 publications

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“…Herpes simplex virus derived glycoproteins B, H, and L, are TLR2 agonists [19]. Indeed, recent studies suggested a strong link between CNS infection with HSV and development of AD in human patients [14] and mice [5]. More commonly, TLR2 agonists are produced by multiple systemic infectious agents affecting patients, including chronic gingivitis [17], skin pathogens, [38] and gut microbiome [47].…”

Section: Discussionmentioning

confidence: 99%

Systemic microbial TLR2 agonists induce neurodegeneration in Alzheimer’s disease mice

Lax

Fainstein

Nishri

et al. 2020

J Neuroinflammation

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Background: Accumulating data suggest a central role for brain microglia in mediating cortical neuronal death in Alzheimer's disease (AD), and for Toll-like receptor 2 (TLR2) in their toxic activation. Amyloid deposition in preclinical AD is associated with microglial activation but not directly with neurodegeneration. We examined in transgenic 5xFAD mice the hypothesis that systemic TLR2 agonists, derived from common infectious agents, may accelerate neurodegeneration in AD. Methods: Microbial wall-derived TLR2 agonists zymosan and lipoteichoic acid were administered intraperitoneally or intracerebroventricularly to 7-month-old wild-type or 5xFAD mice. Immunofluorescent stainings were used to quantify cortical neurons and evaluate tissue reaction. Microglial activation was assessed using functional assays, RNA expression, and FACS analysis. Results: Repeated low-dose systemic administration of zymosan or lipoteichoic acid killed cortical neurons in 5xFAD mice but not in wild-type mice. Direct CNS delivery of a selective TLR2 antagonist blocked the neurotoxicity of systemically administered zymosan, indicating that CNS TLR2 mediates this effect. Systemically administered zymosan crossed the disrupted blood-brain barrier in 5xFAD mice and entered brain parenchyma. By intracerebroventricular delivery, we found a dose-and exposure time-dependent acute neurotoxic effect of the microbial TLR2 agonist, killing cortical neurons. 5xFAD mice exhibited significantly increased vulnerability to TLR2 agonist-induced neuronal loss as compared to wild-type mice. Microbial TLR2-induced neurodegeneration was abolished by inhibiting microglia. The vulnerability of 5xFAD mice brains was mediated by an increase in number and neurotoxic phenotype of TLR2expressing microglia. Conclusions: We suggest that repeated exposure to microbial TLR2 agonists may facilitate neurodegeneration in AD by their microglial-mediated toxicity to the hyper-vulnerable environment of the AD brain.

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Section: Discussionmentioning

confidence: 99%

Systemic microbial TLR2 agonists induce neurodegeneration in Alzheimer’s disease mice

Lax

Fainstein

Nishri

et al. 2020

J Neuroinflammation

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“…Taken together, our findings indicate that a CNS infection without signs of disease can lead to impairments in cognitive functions through local inflammatory responses in the hippocampus. Since chronic neuroinflammation or repeated virus reactivation is associated with neurodegenerative diseases [ 60 ], mild infections of the CNS could display relevant risk factors.…”

Section: Discussionmentioning

confidence: 99%

Langat virus infection affects hippocampal neuron morphology and function in mice without disease signs

Cornelius

Hosseini

Schreier

et al. 2020

J Neuroinflammation

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Background Tick-borne encephalitis virus (TBEV) is an important human pathogen that can cause the serious illness tick-borne encephalitis (TBE). Patients with clinical symptoms can suffer from severe meningoencephalitis with sequelae that include cognitive disorders and paralysis. While less than 30% of patients with clinical symptoms develop meningoencephalitis, the number of seropositive individuals in some regions indicates a much higher prevalence of TBEV infections, either with no or subclinical symptoms. The functional relevance of these subclinical TBEV infections and their influence on brain functions, such as learning and memory, has not been investigated so far. Methods To compare the effect of low and high viral replication in the brain, wildtype and Irf-7−/− mice were infected with Langat virus (LGTV), which belongs to the TBEV-serogroup. The viral burden was analyzed in the olfactory bulb and the hippocampus. Open field, elevated plus maze, and Morris water maze experiments were performed to determine the impact on anxiety-like behavior, learning, and memory formation. Spine density of hippocampal neurons and activation of microglia and astrocytes were analyzed. Results In contrast to susceptible Irf-7−/− mice, wildtype mice showed no disease signs upon LGTV infection. Detection of viral RNA in the olfactory bulb revealed CNS infections in wildtype and Irf-7−/− mice. Very low levels of viral replication were detectable in the hippocampus of wildtype mice. Although wildtype mice develop no disease signs, they showed reduced anxiety-like behavior and impaired memory formation, whereas Irf-7−/− mice were not affected. This impairment was associated with a significant decrease in spine density of neurons in the hippocampal CA1 region of wildtype mice. Microglia activation and astrogliosis were detected in the hippocampus. Conclusion In this study, we demonstrate that subclinical infections by viruses from the TBEV-serogroup affected anxiety-like behavior. Virus replication in the olfactory bulb induced far-reaching effects on hippocampal neuron morphology and impaired hippocampus-dependent learning and memory formation.

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“…Examples of amyloid‐beta accumulating conditions include (i) aged Sgo1 −/+ mice, a cohesinopathy–chromosome instability mouse model (Rao, Farooqui, Zhang et al, ) (photo: Our Aβ IHC results from 18‐ to 24‐month‐old Sgo1 −/+ mice. The magnified panel indicates extracellular “released” Aβ), and (ii) HSV1 infection (e.g., De Chiara et al, ). Photo: Our Aβ IHC results from HSV1‐infected 12‐month‐old C57BL/6 mice (unpublished).…”

Section: The “Amyloid‐beta Accumulation Cycle”mentioning

confidence: 99%

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

et al. 2020

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The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad‐spectrum anticancer drugs. Cyclin‐dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA‐approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid‐beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD‐omics and preclinical animal models provided data supporting the long‐standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re‐entry, leading to the “amyloid‐beta accumulation cycle,” may be a prerequisite for amyloid‐beta accumulation and AD pathology development; (b) AD‐associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the “amyloid‐beta accumulation cycle is an AD drug target” concept is proven, repurposing of cancer drugs may emerge as a new, fast‐track approach for AD management in the clinic setting.

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Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice

Cited by 169 publications

References 69 publications

Systemic microbial TLR2 agonists induce neurodegeneration in Alzheimer’s disease mice

Systemic microbial TLR2 agonists induce neurodegeneration in Alzheimer’s disease mice

Langat virus infection affects hippocampal neuron morphology and function in mice without disease signs

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

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