Temporal Analysis of Infection in Alzheimer’s Disease Models

Infection as a cause of Alzheimer’s disease has been debated for decades; however, the connection between infection and the molecules tau and amyloid beta, which are associated with the hallmarks of the disease, are not clear. Proteins are the machines that largely keep our bodies functioning, and in AD and other neurodegenerative diseases, proteins such as tau and amyloid beta become chemically modified and malfunction. The Steen lab is large-data driven—we collect and mine quantitative protein datasets of approximately 10,000 proteins from human brain tissues and cells using a unique analytical and informatics platform that we developed. Recently, we used this approach to study more than 130 post-mortem patient brain tissue samples with AD, other tauopathies and control tissues. Strikingly, our network analysis of the data showed a strong response for AD patients and identified specific molecules associated with microbial infection. This supports the study from the Moir and Tanzi labs that described a role of amyloid beta peptide as an antimicrobial agent, thereby linking a molecule that is genetically associated with AD as having a role in the response to infection. This and other data in the literature lead us to hypothesize that infection plays a major role in AD. To further investigate this hypothesis, we propose the study of the infection process in both a mouse AD model and a human neuronal cell model to understand the temporal events of infection of neuronal cells at the molecular level. Our proteomics and informatics platform identifies and quantifies a large proteome and currently surpasses any other platform applied to neuronal/brain samples with respect to the depth of the proteome. Thus, the data enables the identification of key molecules responsible for disease. By identifying molecules in the infection process that result in the death of neurons, we can intervene in the progression of disease and cognitive decline.