Abstract
Increasing evidence indicates Chronic Periodontitis (CP) is a comorbidity of Alzheimer’s disease (AD), which is the most common form of age-related dementia, and for the latter, effective diagnostic and treatment strategies are lacking. Although inflammation is present in both diseases, the exact mechanisms and cross-links between CP and AD are poorly understood; and a direct association between the two has not been reported. This study aimed to identify a direct serum proteins link between AD and CP. Two-dimensional differential in-gel electrophoresis was employed to analyze serum samples from 12 CP patients and 12 age-matched controls. Furthermore, to determine the molecular link between CP and AD, neuroblastoma SK-N-SH APPwt cells were treated with 1 μg/ml of lipopolysaccharide from Porphyromonas gingivalis (P.g-LPS). Ten differentially expressed proteins were identified in CP patients. Among them, nine proteins were up-regulated, and one protein was down-regulated. Of the 10 differentially expressed proteins, five proteins were reportedly involved in the pathology of AD: Cofilin-2, Cathepsin B, Clusterin, Triosephosphate isomerase, and inter-alpha-trypsin inhibitor heavy chain H4 (ITI-H4). Western blotting indicated significantly higher expression of Cofilin-2, Cathepsin B, and Clusterin and lower expression of ITI-H4 in the CP group than in the Control group. The serum concentration of Cathepsin B has a good correlation with MMSE scores. Moreover, the protein level of Cathepsin B (but not that of ADAM10 and BACE1) increased significantly along with a prominent increase in Aβ1–40 and Aβ1–42 in the cell lysates of P.g-LPS-treated SK-N-SH APPwt cells. Cathepsin B inhibition resulted in a sharp decrease in Aβ1–40 and Aβ1–42 in the cell lysates. Furthermore, TNF-α was one of the most important inflammatory cytokines for the P.g-LPS-induced Cathepsin B upregulation in SK-N-SH APPwt cells. These results show that CP and AD share an association, while Cathepsin B could be a key link between the two diseases. The discovery of the identical serum proteins provides a potential mechanism underlying the increased risk of AD in CP patients, which could be critical for elucidating the pathophysiology of AD.
Highlights
Alzheimer’s disease (AD) is one of the most common forms of dementia among elderly people and is pathologically characterized by senile plaques and neuro-fibrillary tangles and clinically characterized by progressive deterioration of episodic memory and cognitive decline (Hardy and Higgins, 1992)
The results showed in the context of TNF-α inhibition, P.g-LPS could not up-regulate the protein expression of Cathepsin B, which confirmed it was TNF-α which was responsible for P.g-LPS induced Cathepsin B up-regulation in SK-N-SH APPwt cells (Figures 5C,D)
Several studies have indicated that patients with AD have poorer dental health than age-matched controls, while other studies have confirmed that patients with Chronic Periodontitis (CP) have cognitive defects and even dementia (Pritchard et al, 2017; Dominy et al, 2019)
Summary
Alzheimer’s disease (AD) is one of the most common forms of dementia among elderly people and is pathologically characterized by senile plaques and neuro-fibrillary tangles and clinically characterized by progressive deterioration of episodic memory and cognitive decline (Hardy and Higgins, 1992). CP comprises both gingivitis and periodontitis; for the latter, inflammation is localized in the gingival tissues or the inflammatory process reaches deeper connective and bone tissue, causing bone and attachment loss that may lead to tooth loss (Lang et al, 2009). This local inflammatory process may induce a systemic inflammatory state via mechanisms including dissemination of pro-inflammatory cytokines or bacteria or both from oral to extra-oral sites or even to blood circulation, which may contribute to the exacerbation of several diseases (Martins et al, 2016)
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