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

Abstract

Alzheimer's disease (AD) is the most common type of dementia and characterized by tau hyperphosphorylation, oxidative stress, reactive microglia and amyloid-β (Aβ) deposits. A recent study revealed that Porphyromonas gingivalis infection is associated with amyloid β generation in Alzheimer's disease. Increased Aβ 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 β. Interestingly, meprin β is an alternative βsecretase of the amyloid precursor protein (APP), which together with the -secretase leads to the generation of aggregation-prone N-terminally truncated Aβ2-x peptides. Importantly, identification of a risk gene variant of meprin β (rs173032) for Alzheimer's disease using wholeexome sequencing of the BDR cohort further supports the impact of this alternative βsecretase. Thus, we wondered if increased Aβ levels as a consequence of P. gingivalis colonization into the brain might be due to meprin β activation by RgpB. Here, we demonstrate that i) upon incubation with RgpB the proteolytic activity of meprin β 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 β activity leads to massive generation of Aβ-peptides. In conclusion, our findings would further explain the pathogenesis of P. gingivalis in AD brain.

Alzheimer’s Disease: A Systems View Provides a Unifying Explanation of Its Development

“…In contrast to Ca 2+ , which stabilizes enzyme activity, glycyl-glycine considerably enhances the inactivation rate. RgpB shows proteolytic activity towards APP resulting in degradation of soluble APP ectodomains generated by βand γ-secretases [30]. RgpB is capable of destroying human connective tissues, cell surface proteins and receptors, cytokines, components of the coagulation and complement cascades, heme and iron-binding proteins, immunoglobulins, and proteinase inhibitors as a result of the aforementioned situation [150].…”

“…Epidemiological studies show correlations between AD and periodontitis, an oral disease in which P. gingivalis plays a central role [28]. Various preclinical studies have shown the presence of P. gingivalis to lead to AD cerebral pathologies and cognitive decline [29][30][31]. Recently, traces of this pathogen were discovered in brain legions of AD patients, providing evidence for a possible causal relationship [32].…”

Synthesis and Structure-Activity Relationships of Pyrazole-based Inhibitors of Meprin α and β

“…The protected hydroxamic acid was introduced by coupling of 11 with benzylhydroxylamine. The formation of the pyrazole core was accomplished using a one-pot method reported by Heller et al 39 The 1,3-diketone intermediates were synthesized from the N-benzyloxy-4oxo-4-phenylbutanamide derivatives (12) and either acid chlorides or carboxylic acids and carbonyldiimidazole. The 1,3-diketones were converted in situ into the respective pyrazoles (13 & 14) by subsequent addition of hydrazine monohydrate.…”

“…Meprin α is supposed to act as promigratory protease in the context of colorectal and hepatocytic cancer [1][2][3][4][5][6] and was also linked to vascular diseases like arteriosclerosis, cardiac remodeling and aneurysms, recently [7][8][9] . Meprin β is also involved in cancer cell invasion 10,11 and moreover is able to act as an alternative beta-secretase, contributing to the progression of Alzheimer´s disease via the release of neurotoxic amyloid peptides [12][13][14][15][16][17] . Both proteases act as procollagenases and are involved in the biosynthesis and assembly of collagen fibrils.…”

Expression of TNF, IL1B, and iNOS2 in the neural cell after induced by Porphyromonas gingivalis with and without coating antibody anti-Porphyromonas gingivalis

“…Sophie’s research found the presence of LPS P. gingivalis in the brains of Alzheimer’s patients 3 . The mechanism for invading P. gingivalis bacteria into brain tissue is by penetrating the blood-brain barrier and damaging neuron cells 4 . When entering the central nervous system, these bacteria will first activate defense cells in the brain, namely the microglia, and astrocytes.…”