Varicella Zoster Virus (VZV), responsible for causing chickenpox in children and shingles in the elderly, has long been recognised as a pathogen with wide-ranging impacts on human health. However, emerging research suggests that VZV might play a more insidious role in the development of Alzheimer’s disease (AD), a connection that is both intriguing and concerning. In a recent lecture as part of the Krea Biology Talks series, Professor Ravi Mahalingam delved into the complex relationship between VZV and Alzheimer’s disease, shedding light on how this common virus might contribute to the acceleration of neurodegenerative processes.
The Link Between VZV and Alzheimer’s Disease
VZV is a herpesvirus that remains latent in sensory neurons after the initial infection, only to reactivate later in life as shingles, particularly in the elderly. While shingles is well-known for its painful rash, its association with increased dementia risk, especially Alzheimer’s disease, is less understood. Professor Mahalingam emphasised that understanding this link is challenging due to VZV’s exclusive infectivity in humans, making direct studies difficult.
Simian Varicella Virus as a Model for Alzheimer’s Pathology
To overcome this challenge, researchers have turned to the Simian Varicella Virus (SVV), which produces a disease in primates remarkably similar to VZV in humans. Professor Mahalingam’s research utilised SVV infection in rhesus macaques to explore how viral infection might contribute to Alzheimer’s pathology. Infected macaques developed chickenpox, followed by latency and reactivation under immune suppression. Analysis of blood, tissues, and arteries revealed that SVV infection created an environment conducive to amyloid formation—a hallmark of Alzheimer’s disease.
The findings were striking: SVV antigens co-localised with amyloid deposits not only in peripheral organs like the pancreas and gastrointestinal tract but also in cerebral arteries, a critical site implicated in cerebrovascular diseases associated with Alzheimer’s. These results suggest that varicella infection may accelerate Alzheimer’s progression by increasing the amyloid burden in the brain and vascular system.
The Role of Small Extracellular Vesicles in VZV Pathogenesis
Professor Mahalingam also discussed the role of small extracellular vesicles (sEVs) in VZV pathogenesis. sEVs are membranous structures that can deliver proteins and nucleic acids to distant cells and tissues, altering their function. In the context of VZV infection, sEVs released from infected neurons contain viral and host proteins that contribute to disease spread and immune evasion. Notably, these sEVs are non-infectious yet still promote neuroinvasion of secondary pathogens and suppress the body’s antiviral response, highlighting a novel mechanism by which VZV might contribute to distant pathologies, including those observed in Alzheimer’s disease.
VZV Reactivation and Multi-Organ Disease
VZV reactivation not only increases the risk of neurological complications like stroke but also raises susceptibility to co-infections at sites distant from the original infection. Professor Mahalingam noted that this could be due to the immunosuppressive and vascular disease-associated proteins found in the sEVs released from VZV-infected neurons. These proteins, along with the immediate-early 62 (IE62) protein, may suppress the body’s antiviral response, facilitating the virus’s spread and increasing the risk of central nervous system invasion—a significant concern for Alzheimer’s progression.
Amylin and Alzheimer’s Disease
Another critical aspect of the lecture was the discussion on amylin, a peptide produced in the pancreas alongside insulin. Elevated levels of amylin, similar to amyloid-beta (Aβ) in the nervous system, have been observed in the brains of Alzheimer’s patients. During acute zoster, plasma amyloid levels rise, creating an amyloidogenic environment in both serum and cerebrospinal fluid. This process further increases the risk of Alzheimer’s disease, as amylin can misfold and aggregate, contributing to the amyloid burden in the brain.
Challenges and Future Directions
Despite these findings, Professor Mahalingam highlighted the challenges of further mechanistic studies due to the lack of a suitable animal model that fully recapitulates human VZV disease. While attempts have been made to induce VZV infection in various animal models, including guinea pigs and mice, none have successfully replicated the full spectrum of human disease. However, the use of SVV in rhesus macaques presents a promising model to study emerging risk factors in Alzheimer’s disease.
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