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.

These data (Supplementary Table 2 , Figs. 5-7) show that upregulated AD hippocampal genes match those upregulated by multiple pathogens in immunocompetent cells and that sensors and defenders relating to multiple pathogens are upregulated in the AD brain, blood, or CSF. These involve reactions to many of the pathogens of this study, representing many different classes (bacteria, viruses, fungi, and parasites) and there appears to be no discrimination, or focus on any particular type. This would concord with the multiple and diverse pathogen species that have been detected in the AD brain and with the relationship between the AD genes or the hippocampal transcriptome with multiple pathogen species. In this analysis, a variety of pathogens were used based mostly on their relationship with AD epidemiology, but also to include diverse families (viruses, bacteria, fungi, and protozoa). Those relevant to most AD cases will presumably relate to the most common infections in the elderly. In the US, these include influenza, bacterial pneumonia, urinary tract infection, intra-abdominal infections, gramnegative bacteremia, and infection of pressure ulcers [161, 162] . These are caused by more common bacteria, fungi, and viruses, rather than by more exotic species such as the Bornavirus or T. cruzi. Despite Table 2 . Regions: CP, choroid plexus; Cortical areas (Cx, cortex; Entorhin, entorhinal; Fr, frontal; par, parietal; Temp, temporal; occip, occipital); CSF, cerebrospinal fluid; GVS, granulovacuolar degeneration; HPC, hippocampus; lympho, lymphocytes; macro, macrophages; mcyt, monocytes; mgli, microglia; Mvasc, microvasculature (brain); Neur, neurons; NFT, neurofibrillary tangles; PBMC, peripheral blood mononuclear cells; Plaq, amyloid plaques; Ser, serum; tang, tangles. Antimicrobial peptides and related: AZU1, azurocidin; ␤amy, amyloid-␤; APCS, amyloid P component, serum; Calpro, calprotectin ( = S100A8+S100A9); CHGA, chromogranin A; DCD, dermcidin; ␣defs or ␤defs, unspecified alpha or beta defensins: CAMP, cathelicidin antimicrobial peptide (LL-37); CHI3L1, chitinase 3 like 1 (aka YKL-40); Defensins, DEFA's, DEFB's: ELANE, elastase; HAMP, hepcidin; HTN1, histatin 1; IAPP, islet amyloid polypeptide (Amylin); LCN2, lipocalin 2; LTF, lactotransferrin; S100's, S100 calcium binding protein; SNCA, alpha synuclein. Pattern recognition receptors: CD14; CD36; C-type lectin, CLECs; MRC1, mannose receptor C type 1; Toll-like receptors, TLR1 to 10. Viral detectors and antiviral: DEAD box proteins, DDXs; EIF2AK2, eukaryotic translation initiation factor 2 alpha kinase 2 (pkr); SIRTs, sirtuins; 25-and 27-OH-cholesterol, 25- the potential relationship of so many pathogens to AD, their cerebral entry will still also depend upon on the multiple and manageable environmental factors that disrupt or prevent BBB malfunction. Until more extensive studies of the blood and brain microbiomes in AD, the relative importance of individual or multiple species can only be speculative. A recent investigation of the gut bacterial microbiome in elderly cognitive impairment, associated with brain amyloidosis, reported an increase in the abundance of pro-inflammatory Escherichia/Shigella taxa and a reduced abundance of an anti-inflammatory taxon; E. rectale. These changes were associated with a pro-inflammatory blood cytokine profile in subjects with brain amyloidosis [163] , but to date there have been few brain microbiome studies in AD, or studies of the peripheral AD virome