title: A Bacterial Component to Alzheimer's-Type Dementia Seen via a Systems Biology Approach that Links Iron Dysregulation and Inflammagen Shedding to Disease.
abstract: The progression of Alzheimer's disease (AD) is accompanied by a great many observable changes, both molecular and physiological. These include oxidative stress, neuroinflammation, and (more proximal to cognitive decline) the death of neuronal and other cells. A systems biology approach seeks to organize these observed variables into pathways that discriminate those that are highly involved (i.e., causative) from those that are more usefully recognized as bystander effects. We review the evidence that iron dysregulation is one of the central causative pathway elements here, as this can cause each of the above effects. In addition, we review the evidence that dormant, non-growing bacteria are a crucial feature of AD, that their growth in vivo is normally limited by a lack of free iron, and that it is this iron dysregulation that is an important factor in their resuscitation. Indeed, bacterial cells can be observed by ultrastructural microscopy in the blood of AD patients. A consequence of this is that the growing cells can shed highly inflammatory components such as lipopolysaccharides (LPS). These too are known to be able to induce (apoptotic and pyroptotic) neuronal cell death. There is also evidence that these systems interact with elements of vitamin D metabolism. This integrative systems approach has strong predictive power, indicating (as has indeed been shown) that both natural and pharmaceutical iron chelators might have useful protective roles in arresting cognitive decline, and that a further assessment of the role of microbes in AD development is more than highly warranted.
authors.affiliation: Department of Physiology, Faculty of Health Sciences, University of Pretoria, Arcadia, South Africa.
authors.forename: Etheresia
authors.initials: E
authors.lastname: Pretorius
authors.affiliation: Department of Physiology, Faculty of Health Sciences, University of Pretoria, Arcadia, South Africa.
authors.forename: Janette
authors.initials: J
authors.lastname: Bester
authors.affiliation: School of Chemistry, The University of Manchester, Manchester, Lancs, UK.|The Manchester Institute of Biotechnology, The University of Manchester, Manchester, Lancs, UK.|Centre for Synthetic Biology of Fine and Speciality Chemicals, The University of Manchester, Manchester, Lancs, UK.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kell
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D000818:Animals; D018407:Bacterial Physiological Phenomena; D006801:Humans; D007501:Iron / Q000378:metabolism*; D049490:Systems Biology
chemical_list: D007501:Iron
keywords: Alzheimer’s disease; LPS; bacteria; dormancy; dysbiosis; eryptosis; iron; systems biology; ultramicroscopy