PC‐001: Addressing Koch's postulates: The role of herpes simplex virus in Alzheimer's disease

Background: It has been known since the early 20 the century that infectious organisms, such as the Treponemal Spirochete causing syphilis, induce Abeta plaques in the brain. Recent evidence shows similar Abeta with Borrelia Burgdorferi, the causative agent for Lyme disease. Others have proposed that the neurotropic herpes simplex virus (HSV), which infects 85% of aging Americans, is a causative agent in Alzheimer’s disease (AD), yet examination of AD brains for HSV has been inconclusive. Recent in vitro evidence shows that HSV associates with APP inside cells and induces increased APP and Abeta production (Cheng...Bearer, 2011). To address Koch’s 3rd postulate, that HSV causes AD pathology, we are investigating whether acute HSV brain infections in human subjects induce the production of Abeta plaques, neurofibrillary tangles, and/or neuritic plaques; the pathognomonic hallmarks of AD. Methods: Pathological specimens obtained from 3 diagnosed cases of HSV encephalitis (HSE) across the lifespan (subjects aged 9d, 8yr, and 76yr old) were probed by immuno-staining for Abeta, phospho-tau, neuritic plaques, and inflammation, as well as by DNA analysis for HSV type, location, viral load and host ApoE alleles. Colocalization of virus with AD pathology was determined by quadruple-color immunofluorescence imaged by deconvolution microscopy with 50 nm resolution. Subjects were genotyped for ApoE and HSV typing was performed by PCR, RFLP, and sequencing according to protocols developed in the Bearer lab (Brown, Bearer and Donohue, 2010). Results: We found Abeta deposition near viral particles in all subjects, including the 9d old infant and the 8y old child. HSV was also found in endothelial cells of the vasculature in all cases. In the 76y old, both viral typeswere present. Viral particles and plaques were not always coincident. Even in the 76y old, phospho-tau staining was rare. Distribution of plaques throughout the brain correlated with viral activity with sparing of the hippocampus, which is inconsistent with typical AD presentation. Conclusions: Using a novel strategy, we show that active HSV infections in the brain result in Abeta deposition. In acute stages, neurofibrillary tangles are rare, suggesting that this pathologic feature requires time or other cofactor(s) to develop. We thus satisfy Koch’s 3 rd postulate: the HSV causes Abeta deposition that would in concert with other factors lead to an AD-like pathology.