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 promiscuous defensive agents include antimicrobial agents (A␤ and cathelicidin/LL-37), leukotriene B4 and its synthesizing enzyme 5-lipoxygenase (ALOX5), complement receptors (CR3, CR4), and the membrane attack complex, Fc gamma receptors, interferon-gamma and TLRs (TLR1, 2, 3, 4, 7, and 9). Indoleamine dioxygenase (IDO1) and its derivative, the neurotoxic quinolinic acid also belong to this group. More selective antiviral agents (HSV-1) include the oxysterols, 25and 27-hydroxycholesterol and their synthesizing enzymes (CH25H and CYP17A1), DDX58/RIG-1, EIF2AK2, and sirtuins. Those related to C. albicans include the C-type lectin CLEC7A, the mannose receptor MRC1, CD36, and the antimicrobial peptides, chromogranin A, dermcidin, histatin, and synuclein. Relatively selective spirochete defense is exemplified by neutrophil elastase, CD14, and TLRs (TLR5, TLR8). This analysis suggests that the antimicrobial alerts in AD reflect a polymicrobial origin. It should, however, be recognized that such specificity is not absolute for other viral, fungal, or bacterial species. For example, in relation to B. burgdorferi selective agents, TLR5 also recognizes bacterial flagellin (Refseq) and TLR8 recognizes single stranded viral RNA [159] . Alpha-synuclein (C. albicans-selective) has antifungal effects, and is also antibacterial (Escherichia coli and Staphylococcus aureus) [160] .