Is there a link between genetic defects in the complement cascade and Porphyromonas gingivalis in Alzheimer's disease?

Abstract

Defects, as determined by Genome-Wide Association Studies (GWAS), in the complement cascade of innate immunity have been suggested to play a key role in Alzheimer's disease (AD). These defective genes encode sub-component 1s (C1s), complement receptor 1, complement component 9, and clusterin, a fluid-phase regulatory protein. A dysregulated complement cascade has been shown to relate to cell activation, defective complement mediated clearance and possible cognitive decline in AD patients. Porphyromonas gingivalis, a putative keystone pathogen of periodontal disease, has been reported to be associated with human AD. The inflammatory burden following experimental oral infection in mice and putative entry of this bacterium into the brain appears to drive the formation of amyloid-beta plaques and neurofibrillary tangles with loss of cognition. P. gingivalis is a master of immune subversion in this inflammatory cascade and may establish microbial dysbiosis where it is located. Here we discuss if P. gingivalis may enhance the detrimental effects of the defective GWAS complement cascade protein genes.

Keywords: GWAS; P. gingivalis; complement; dysbiosis; immune subversion; periodontitis.

Figure 1.

Illustration showing the effects of P. gingivalis oral infection and its local subversive effect on degradation of opsonins with IgG, C1q, iC3b and MAC to evade complement mediated death and at the same time amplify inflammation. In the brain, a nerve cell infected by P. gingivalis itself or internalization of outer membrane vesicles (microbullets) initiate microglial surveillance. This results in an inflammatory activity when the host cell encounters Aβ (in its capacity as an AMP) opsonized by IgG, C3b and iC3b opsonins in the paths of the neuronal processes. Due to polymorphic defects in the complement regulating proteins, and the inability of microglia to clear Aβ, inflammation is thought to be amplified and sustained

Figure 2.

A ‘frustrated innate immune system’ in the inflamed Alzheimer’s disease brain. This contribution is from multiple sources including the polymorphic complement component genes [–28], the APOE variant [8], blood-brain barrier defects [30], pathogen entry, and Aβ as a defense peptide released in response to infections [24]. All these contribute to complement activity, cell activation, defective phagocytosis and chronic inflammation [15]. There would be clinical value in inhibiting all three main pathways of complement at the C3 stage