The Alzheimer’s disease associated bacterial protease RgpB from P. gingivalis activates the alternative β-secretase meprin β thereby increasing Aβ generation

Abstract

Alzheimers disease (AD) is the most common type of dementia and characterized by tau hyperphosphorylation, oxidative stress, reactive microglia and amyloid-{beta} (A{beta}) deposits. A recent study revealed that Porphyromonas gingivalis infection is associated with amyloid {beta} generation in Alzheimers disease. Increased A{beta} levels, tau degradation and neuronal toxicity were observed as a consequence of ginigipain R (RgpB) activity, a cysteine protease constitutively secreted by P. gingivalis. Of note, we previously identified RgpB as a potent activator of the metalloproteinase meprin {beta}. Interestingly, meprin {beta} is an alternative {beta}-secretase of the amyloid precursor protein (APP), which together with the {gamma}-secretase leads to the generation of aggregation-prone N-terminally truncated A{beta}2-x peptides. Importantly, identification of a risk gene variant of meprin {beta} (rs173032) for Alzheimers disease using whole-exome sequencing of the BDR cohort further supports the impact of this alternative {beta}-secretase. Thus, we wondered if increased A{beta} levels as a consequence of P. gingivalis colonization into the brain might be due to meprin {beta} activation by RgpB. Here, we demonstrate that i) upon incubation with RgpB the proteolytic activity of meprin {beta} at the cell surface of transfected HEK cells or of endogenously expressed enzyme in SH-SY5Y neuroblastoma cells was significantly increased, and that ii) RgpB-mediated increase in meprin {beta} activity leads to massive generation of A{beta}-peptides. In conclusion, our findings would further explain the pathogenesis of P. gingivalis in AD brain.