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.

Some pathogens can also circumvent the BBB by direct attack. For example, certain strains of neuroinvasive B. burgdorferi are known to be able to translocate across the BBB initially via anchoring to host proteins on brain microvascular endothelial cells and subsequently via activation of metalloproteases that degrade extracellular matrix and intercellular junctions [28] . C. pneumoniae infects blood vessels and monocytes in the AD brain, and also promotes the invasion of the infected monocytes through human brain endothelial cells indicating BBB breakdown [29] . The fungal pathogen C. neoformans uses a Trojan horse strategy where infected phagocytes cross brain microendothelial barriers [30] . This pathogen may also actively disrupt BBB function be secreting fungal proteases [188, 189] . P. gingivalis also disrupts epithelial barrier function via secreted proteases (gingipains) that degrade cadherins (CDH1, CDH2,CDH5) as well as occludin, beta-and gamma-catenins, paxillin, and integrins (ITGA3, ITGB1, ITGB4) [190] [191] [192] . Gingipains have been detected in the hippocampal microvasculature of P. gingivalis-infected APOE (-/-) mice and likely contribute to impaired BBB integrity and to the cerebral invasion of P. gingivalis in this model [27] . The prevalence of periodontitis increases with age [193] ; this is again a factor that would limit effects on BBB function to the aged. Any pathogen that so disrupts the BBB might be expected to influence invasion by others.