Alzheimer's disease (AD) is characterized by two hallmark pathologies. The first is accumulation of amyloid-beta peptide (Abeta) outside neurons as insoluble amyloid plaques. The second is aggregation inside of neurons of tau protein as filamentous structures called neurofibrillary tangles. High amyloid loads in brain induce tauopathy and amyloid/tauopathy together appear to cause the neurodegeneration associated with Alzheimer's disease (AD).
The aggregation of Abeta and tau was thought to be intrinsically abnormal, with no physiological function and leading only to neuron-damaging pathology. However, we recently demonstrated that Abeta is a natural antibiotic that protects against infection. Moreover, the normal protective actions of Abeta involve the peptides’ aggregation and eventual entrapment of invading pathogens within amyloid plaques. This raises the possibility of an infection etiology for amyloid plaque accumulation.
The infection hypothesis for AD has a long history (Alois Alzheimer, who first described AD in 1907, proposed an infection etiology for the disease). However, only recently has the hypothesis drawn widespread interest among AD researchers. The increased focus on an infection etiology for AD has been driven in part by the recent identification of multiple links between Alzheimer's disease and immunity genes, and our own findings on the antibiotic role for Abeta and amyloid plaques. During the last 12 months we have been investigating the possible role herpes simplex 1 (HSV-1) virus may play in inducing amyloid plaques using animal models. HSV-1 is the pathogen most strongly linked to AD pathology. Our findings confirm Abeta protects against HSV-1 infection and that the invading virus particles are trapped and inactivated by amyloid plaques.
Here we request an additional six months of funding for our study to investigate a novel model of AD pathology that has emerged from our findings. In this model we will test if HSV-1 infection can lead to amyloid plaque generation that, in turn, drives tau aggregation and generates neurofibrillary tangles. This would, for the first time, serially link viral infection, amyloid plaque deposition and neurofibrillary tangle generation in a single model. We believe confirmation of our model would be a significant advance in understanding the possible role of infection in AD and likely impact current, and future, treatment strategies.