Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion as Determinant Factors in Alzheimer’s Disease

Carter, Chris J.

Genes misregulated in the AD hippocampus are those reported from a postmortem microarray study [83] . Up-and downregulated genes (n = 2,879) were combined for comparison with the pathogen interactomes. The upregulated genes (n = 1,690) from this AD hippocampal study contain the pathways relevant to pathogens and immune activation (inflammation, complement activation and the defense response) [83] and these were chosen for comparison with upregulated genes from infection datasets at the Molecular signatures database (MSigDB; http:// software.broadinstitute.org/gsea/msigdb/index.jsp). MSigDB contains several thousand microarray datasets which can be compared against the various AD inputs [96] . Infection related datasets, and those related to TLR ligands, were identified using search terms (e.g., infection, virus, bacteria, TLR, LPS, etc.). Microarray viral infection datasets (upregulated gene sets) from the gene expression omnibus (GEO) [108] were also downloaded from the Harmonizome database (http://amp.pharm.mssm.edu/ Harmonizome/) from the Ma'ayan laboratory of computational systems [109] . For the searched gene sets, most of the data outputs were restricted at source (by MSigDb or GEO) to the top upregulated genes (usually ∼ 200-300).