Genetic, transcriptome, proteomic and epidemiological evidence for blood brain barrier disruption and polymicrobial brain invasion as determinant factors in Alzheimer’s disease

Abstract

Multiple pathogens have been detected in Alzheimer’s disease (AD) brains. A bioinformatics approach was used to assess relationships between pathogens and AD genes (GWAS), the AD hippocampal transcriptome and plaque or tangle proteins. Host/pathogen interactomes (C.albicans, C.Neoformans, Bornavirus, B.Burgdorferri, cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza, C.Pneumoniae, P.Gingivalis, H.Pylori, T.Gondii, T.Cruzi) significantly overlap with misregulated AD hippocampal genes, with plaque and tangle proteins and, except Bornavirus, Ebola and HERV-W, with AD genes. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi or protozoa in immunocompetent blood cells. AD genes are enriched in bone marrow and immune locations and in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance. The age of AD patients implies resistance to infections afflicting the younger. APOE4 protects against malaria and hepatitis C, and immune/inflammatory gain of function applies to APOE4, CR1, TREM2 and presenilin variants. 30/78 AD genes are expressed in the blood brain barrier (BBB), which is disrupted by AD risk factors (ageing, alcohol, aluminium, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolaemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption and smoking). The BBB and AD benefit from statins, NSAIDs, oestrogen, melatonin and the Mediterranean diet. Polymicrobial involvement is supported by the upregulation of pathogen sensors/defenders (bacterial, fungal, viral) in the AD brain, blood or CSF. Cerebral pathogen invasion permitted by BBB inadequacy, activating a hyper-efficient immune/inflammatory system, betaamyloid and other antimicrobial defence may be responsible for AD which may respond to antibiotic, antifungal or antiviral therapy.

Bacterial DNA promotes Tau aggregation

“…The analysis of the sizes of DNA molecules used in the study revealed no correlation between the sizes of DNA bands and different effects of DNA from different microorganisms on tau aggregation. Further studies need to be done to investigate the molecular mechanism by which DNA from some species of bacteria produce effect while others do not alter tau aggregation.The findings obtained in the present work indicate that DNA may play a previously overlooked role in the propagation of tau protein misfolding and AD pathogenesis, providing a new conceptual framework that positions the compromised blood brain and intestinal barriers as important sources of microbial DNA in the brain; indeed, altered gut permeability and disrupted BBB could precede AD development 64 . Moreover, we have recently described a clinical case showing improvement of cognition in an AD patient following therapy with deoxyribonuclease I enzyme, that cleaves cell-free DNA 65,66 .…”

“…This is interesting considering that several lines of evidence indicate that intestinal bacteria play a key role in the pathogenic cascade of both PD and AD 18,19 . Supporting the hypothesis that microorganisms play role in AD pathogenesis, HHV-1, Porphyromonas gingivalis, Candida spp., Escherichia coli, Chlamydophila pneumoniae, and Borrelia burgdorferi have been detected in the cerebrospinal fluid (CSF) and postmortem brains of individuals with AD [20][21][22][23][24][25] . Moreover, the cell wall components of C.pneumoniae, an obligate intracellular bacteria, and E. coli, which can act as a facultative intracellular parasite, have been found within neurons, suggesting that some of these bacteria could directly invade neurons 26,27 .…”

The Porphyromonas gingivalis/Host Interactome Shows Enrichment in GWASdb Genes Related to Alzheimer's Disease, Diabetes and Cardiovascular Diseases

“…The weakened BBB may enable the cerebral entry of other pathogens (viral, fungal, and bacterial origin), that are detected in AD brains. The leaky BBB might also favor the entry of other environmental toxins (e.g., pesticides, pollution, aluminum, or heavy metals) that have been associated with Aβ fibrils in AD (Carter, 2017 ). In addition, the P. gingivalis interactome was highly enriched in cerebral arterial genes, which further supports the correlation with BBB damage.…”

Exploring the Association between Alzheimer’s Disease, Oral Health, Microbial Endocrinology and Nutrition

“…AD has an inherited early-onset form (O’Brien and Wong, 2011 ): the late onset form also has high heritability but is also associated with numerous pathogens, many of which are able to promote the key features of AD in laboratory models. Interestingly, AD related genes from Genome Wide Association Studies overlap with the host genes employed by several pathogens, including P. gingivalis , suggesting that susceptibility genes and pathogens may condition each other’s disease promoting effects (Carter, 2017 ).…”