Susceptibility to gingipains and transcriptomic response to P. gingivalis highlights the ribosome, hypothalamus, and cholinergic neurons

Abstract

Porphyromonas gingivalis, a keystone species in the development of periodontal disease, is a suspected cause of Alzheimer's disease. This bacterium is reliant on gingipain proteases, which cleave host proteins after arginine and lysine residues. To characterize gingipain susceptibility, we performed enrichment analyses of arginine and lysine proportion proteome-wide. Proteins in the SRP-dependent cotranslational protein targeting to membrane pathway were enriched for these residues and previously associated with periodontal and Alzheimer's disease. These ribosomal genes are up-regulated in prefrontal cortex samples with detected P. gingivalis sequences. Other differentially expressed genes have been previously associated with dementia (ITM2B, MAPT, ZNF267, and DHX37). For an anatomical perspective, we characterized the expression of the P. gingivalis associated genes in the mouse and human brain. This analysis highlighted the hypothalamus, cholinergic neurons, and the basal forebrain. Our results suggest markers of neural P. gingivalis infection and link the gingipain and cholinergic hypotheses of Alzheimer's disease.

Donor-Specific Transcriptomic Analysis of Alzheimer's Disease-Associated Hypometabolism Highlights a Unique Donor, Ribosomal Proteins and Microglia

“…The authors of this study speculate that the SRP-dependent protein targeting genes relate the gingipain hypothesis of AD causation that implicates Porphyromonas gingivalis ( Dominy et al, 2019 ). A second study supports this connection by showing that the ER translocation genes are upregulated in cortical samples with detected P. gingivalis sequences and are enriched for the arginine and lysine residues that the gingipain proteases cleave at ( Patel et al, 2020 ). By performing neuroanatomical analyses, this study also discovered that the ER translocation genes are highly expressed in hypothalamus, cholinergic neurons, and the basal forebrain.…”