Recent studies suggest that neurotropic viruses such as herpes simplex virus type 1 (HSV-1) may influence the development of neurodegenerative diseases, including Alzheimer’s disease. A research team has now successfully broken the pipeline between viral infection and Alzheimer’s disease using an experimental drug candidate: ALT001. The study was published on March 31 in the journal Theranostics. Read on for more information on the research, led by Dr. Ok Sarah Shin, a professor in the Department of Convergence Medicine at Korea University College of Medicine (KUCM).
ALT001 Counteracts Long-Term Impacts of HSV-1
Neurotropic viruses such as HSV-1 can cause central nervous system diseases, particularly when the viruses are allowed to replicate without intervention. The neurological effects are linked to the viruses’ neuroinvasive and neurovirulent properties. The association between viral infection and neurodegenerative disease is well-documented, particularly in the case of HSV-1. However, researchers have been uncertain about the precise mechanisms by which HSV-1 infection accelerates neurodegenerative phenotypes. Dr. Shin’s team sought to identify the precise association between viral infection and Alzheimer’s disease.
They didn’t just succeed; they also blocked the connection using the new drug candidate ALT001, a mitophagy enhancer that effectively moderated the virus’s neurologic impact. To achieve these results, the team relied on several cell systems, including microglia, human-derived microglia, microglia-neuron co-culture models, and artificial mini-brain models called organoids.
Exploring the Neurological Impacts of HSV-1
To identify the association between HSV-1 and neurologic disease, the research team first explored the effects of HSV-1 infection on microglia, the brain’s immune cells. They began by generating cerebral organoids from human-induced pluripotent stem cells (hiPSCs). This allowed the researchers to observe the effects of HSV-1 on the microglia in real time.
Using the organoids, the team confirmed that HSV-1 infection disrupts mitophagy. This crucial process works within the cells to remove damaged mitochondria. By disrupting mitophagy, the infection was essentially impairing mitochondrial function. The team also found that HSV-1 interferes with another key neurologic process: phagocytosis, the process of clearing debris out of the cell, including amyloid aggregates. These aggregates are protein clumps within the brain, often a hallmark of neurodegenerative diseases like Alzheimer’s disease.
Evaluating ALT001 as a Mitophagy Enhancer
After observing the impact of HSV-1, the team investigated the potential of ALT001 as an antiviral drug. Per the study, the drug is a mitophagy enhancer previously developed to improve cognitive impairment in mouse models of AD by “inducing mitochondrial biogenesis and stimulating ULK1/Rab9-dependent mitophagy.” As mentioned above, HSV-1 disrupts mitophagy; therefore, by stimulating mitophagy, the team hoped to modulate various immune responses.
ALT001 was able to increase HSV-1-altered clearance of amyloid aggregates in microglia. A decrease in Aβ plaques was observed, “as demonstrated by immunofluorescence staining with Aβ or 6E10 antibody, similar to the results from microglia-neuron co-culture model.”
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Based on these findings, ALT001 is a promising candidate capable of suppressing HSV-1 infection while also alleviating neuroinflammation. By improving mitophagy function, the drug effectively inhibited viral replication while also reducing neuroinflammatory responses. The drug is still considered experimental; however, with further research, it could be a viable option for clinicians hoping to reduce the long-term neurological impacts of HSV-1 and similar neurotropic viruses.
Scantox Neuro provides advanced research services using cerebral organoids to model AD-like pathologies. In addition, we offer primary mouse microglia and organotypic hippocampal brain slices to model neuroinflammation, as well as various platforms to study phagocytosis and measure Aβ aggregation. Several in vivo models and related analysis methods are also available to study Alzheimer’s disease.
Check out Scantox Neuro’s recent webinar “How 3D Organoids Are Shaping the Future of Neuro Drug Discovery“ to learn more about this fascinating and highly translational research tool.
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