Chronic Viral Neuroinfection Mediates Amyloid Beta Deposition in Transgenic Alzheimer’s Disease Mice

The hallmark pathology in Alzheimer’s disease is deposition of amyloid beta peptide in brain as insoluble amyloid. Amyloid beta typically is characterized as a functionless byproduct of metabolism with an intrinsically abnormal propensity for self-association that drives AD pathology. However, antimicrobial peptides are a family of critically important natural antibiotics that self-associate and generate amyloids as part of their normal protective activities. Our recent report on amyloid beta’s protective actions against infection suggest the protein may be an antimicrobial peptide. Our findings revealed aggregation and generation of amyloid are important parts of amyloid beta’s role in immunity, mediating the capture and neutralization of pathogens in brain.

In our experiments, genetically modified cells, nematode worms, fruit flies and AD mice expressing human amyloid beta were protected from infection by amyloid-mediated entrapment of the invading pathogens. Our findings raise the intriguing possibility that chronic neuroinfection may be driving amyloid beta amyloid deposition in AD brain. Evidence also has begun to emerge of high microbial burdens in the brain of AD patients, with neurotropic viruses the pathogens most frequently linked to the disease. New data generated with our collaborators at Mount Sinai (laboratories of Eric Schadt, Sam Gandy and Joel Dudley) show brain regions showing AD pathologies contain high levels of genetic material from herpesviridae viruses. Our preliminary studies have confirmed herpes viruses can seed amyloid beta amyloid deposition in experimental AD models.

We are currently exploring a novel theoretical amyloidosis model in which sustained, elevated replication by herpesviridae enhance amyloidosis, accelerating the cascade of pathologies that lead to neurodegeneration and dementia. Our planned studies will characterize herpes-seeded amyloid generation in a 3-dimensional human neural cell culture system (dubbed Alzheimer’s in a Dish in recent media reports). In addition, we will develop a humanized experimental AD mouse model that can be infected by the species of herpes virus we identified as involved in Alzheimer’s disease. We believe our proposed study will add significantly to an emerging model of a protective/harmful duality to amyloid beta’s activities in brain, as well as better inform current and future AD therapeutic strategies aimed at preventing pathological amyloid beta accumulation.