Porphyromonas Gingivalis May Seek the Alzheimer's Disease Brain to Acquire Iron from Its Surplus

Abstract

Iron accumulates in the brain of subjects with Alzheimer's disease (AD). Here it promotes the aggregation of amyloid-β plaques in which it is abundant. Iron induces amyloid-β neurotoxicity by damaging free radicals and causing oxidative stress in brain areas with neurodegeneration. It can also bind to tau in AD and enhance the toxicity of tau through co-localization with neurofibrillary tangles and induce accumulation of these tangles. Porphyromonas gingivalis is a key oral pathogen in the widespread biofilm-induced disease "chronic" periodontitis, and recently, has been suggested to have an important role in the pathogenesis of AD. P. gingivalis has an obligate requirement for iron. The current paper suggests that P. gingivalis seeks the AD brain, where it has been identified, to satisfy this need. If this is correct, iron chelators binding iron could have beneficial effects in the treatment of AD. Indeed, studies from both animal AD models and humans with AD have indicated that iron chelators, e.g., lactoferrin, can have such effects. Lactoferrin can also inhibit P. gingivalis growth and proteinases and its ability to form biofilm.

Keywords: Biofilm; brain; immunity; iron dysregulation; iron requirement; senescence.

Fig. 1

Schematic presentation of amyloid β (Aβ)-heme complex formation based on published investigations on the complexation of free heme by Aβ. Interaction is proposed to mainly take place between heme and the N-terminal part of the peptide. While one peptide is mainly involved in the coordination of the heme iron at the distal heme site via H13, a second peptide may coordinate at the proximal heme site to provide R5 and Y10, which are responsible for the subsequent peroxidase activity of the complex. Collected from [72].

Fig. 2

Orthographic view of the modeled lactoferrin (LF)-RgpB complex. The solvent-accessible surface of RgpB is green, the dark blue space-filling atom is the zink ion bound to the catalytic histidine (His²⁴⁴) of RgpB. LF is illustrated as a ribbon structure (β-strand in yellow, α-helix in magenta, and coil in cyan). The side-chains of residues that moved to within 3 Å of RgpB during the dynamics simulation are shown as “capped sticks”. The location of the atoms of the RgpB inhibitor, DFFR-chloromethylketone, is shown by red-space filling atoms (from: [89] Permission granted by RightsLink/ASM)