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.

The upregulated hippocampal genes in AD were also enriched in infection datasets for numerous bacteria as well as to fungi (C. albicans and C. neoformans) and in those related to bacterial endotoxin or sepsis and to nematode/trematode or protozoan infection datasets (FDR p < 0.05) (Fig. 6 ). This also applied to diverse LPS datasets and responses to TLR ligands, CpG oligonucleotide (a ligand for TLR9, which mediates cellular response to unmethylated CpG dinucleotides in bacterial DNA or R848 (a ligand for TLR7/TLR8 both of which recognize RNA released from pathogens that enter the cell by endocytosis [150] ) (Fig. 6) . With the exception of H. pylori, P. gingivalis and B. burgdorferi, and C. albicans or C. Neoformans, none have been implicated in AD. Diverse pathogen sensors and defenders relating to bacteria, viruses, parasites, or fungi are upregulated in the AD brain, blood, or CSF The data presented above shows that the hippocampal transcriptome in AD matches that induced by numerous pathogens. The misregulated genes include many related to inflammation, complement activation and the immune system that could relate to many pathogens but also to other neurotoxic promoters. Within the immune system there is a specific branch that is more specifically dedicated to pathogens. This involves pattern recognition receptors, sensors that detect viral DNA or RNA, and antimicrobial defensins, inter alia. These sense cell wall components of bacteria, fungi, or protozoa (TLRs, C-type lectin receptors, and NOD-like) [151, 152] . Others are designed to sense viral DNA or RNA. These include intracellular TLRs (TLR3, 8, 9) , EIF2AK2 (eukaryotic translation initiation factor 2 alpha kinase 2), often known as pkr, RIG-I (coded by retinoic acid-inducible gene 1 = DDX58), MDA5 (Melanoma Differentiation-Associated protein; coded by IFIH1) and LGP2 (coded by DEXH-box helicase 58 = DHX58) [150, 153, 154] . Indoleamine 2,3-dioxygenase 1 (IDO1) diverts tryptophan metabolism to N-formyl-kynurenine; (away from serotonin production). IDO1 upregulation is an important defense mechanism against pathogenic bacteria, many of which rely on host tryptophan. This IDO1 response is also deleterious to other pathogens and parasites, including T. gondii, and to a number of viruses, including HSV-1 and other herpes viruses. Quinolinic acid produced by IDO1 activation is neurotoxin acting via N-methyl-D-aspartate receptors [155] . Kynurenine and kynurenic acid, also produced by IDO1 activation, are ligands for the aryl hydrocarbon receptor, which plays an important role in antimicrobial defense and immune regulation [156] . In relation to viruses, the oxysterols 25-hydroxycholesterol and 27-hydroxycholesterol have also recently emerged as broad-spectrum antiviral agents inhibiting the replication of enveloped and non-enveloped viruses [157] . Sirtuins (SIRT1-7) also have broad spectrum antiviral activity against DNA and RNA viruses [158] .