Contribution of the Virome to Alzheimer's pathogenesis

阿尔茨海默病（AD）是一种广泛存在的年龄相关性痴呆，病因不明，其特征为

Alzheimer’s disease (AD) is a widespread age-related dementia of unknown etiology characterized by neuronal loss, atrophy, and aggregation of beta amyloid (neuritic plaques) and microtubule associated tau proteins (neurofibrillary tangles) in the brain. The major gap in our knowledge is what triggers AD pathogenesis. While deposition of these proteins are thought to play an important role in the pathogenesis of AD, the presence of these aggregates is not sufficient to cause AD. Both humans and experimental animal models can exhibit one or both of these neuropathological changes without cognitive impairment. Thus, there has been increasing effort to identify other risk factors, including infectious agents, that together with protein aggregation could fully explain the etiology of this multifactorial disease. In particular, there is evidence that infection by viral pathogens such as members of the Herpesviridae family of viruses could be risk factors for developing AD. However, like protein aggregates, these viruses are also found in a significant number of healthy individuals and are not consistently enriched in the brains of AD patients. Adequately powered and unbiased studies testing for viral genetic material in AD patients and carefully selected control subjects are needed to establish viral infection as a genuine risk factor. In addition, mechanistic experiments investigating the role of these agents in the pathogenesis of AD are needed in order to reconcile infectious etiologies with more established risk factors such as aging and pathological protein aggregation. As part of the parent DP1 grant, we have developed an unbiased target-enrichment deep-sequencing platform, ViroFind, for identifying all viruses known to infect humans in clinical tissue samples, including post mortem brains- the entire Virome. Our preliminary data indicate that adeno-associated virus (AAV) is enriched in the cerebral cortex of AD patients. Our long term goals are to decipher the pathogenesis of AD. Our overall objectives are to characterize the entire virome in the brain of AD patients using ViroFind. Our central hypothesis is that known viruses, viruses variants, or yet unknown viruses, are able to reach the CNS and remain latent by hiding into neurons, thereby escaping detection from the immune system. Recurrent reactivations during aging triggers an immune and inflammatory reaction with production of Aβ, which leads over the years to AD in certain individuals with genetic predisposition. The rationale is that these proposed pilot studies will enable us to develop an initial understanding of all the viral strains present in AD brains, as well as their cellular localization and whether they are latent or replicating.To verify this hypothesis, we will carry out the following Specific Aim: Aim 1. Determine whether viral infection correlates with the loss of adult neurogenesis in the human hippocampus and whether these factors are associated with the development of AD.