Abstract
Accumulation of amyloid-β (Aβ) in the brain is a central component of pathology in Alzheimer's disease. A growing volume of evidence demonstrates close associations between periodontal pathogens including Porphyromonas gingivalis (P. gingivalis) and Treponema denticola (T. denticola) and AD. However, the effect and mechanisms of T. denticola on accumulation of Aβ remain to be unclear. In this study, we demonstrated that T. denticola was able to enter the brain and act directly on nerve cells resulting in intra- and extracellular Aβ1-40 and Aβ1-42 accumulation in the hippocampus of C57BL/6 mice by selectively activating both β-secretase and γ-secretase. Furthermore, both KMI1303, an inhibitor of β-secretase, as well as DAPT, an inhibitor of γ- secretase, were found to be able to inhibit the effect of T. denticola on Aβ accumulation in N2a neuronal cells. Overall, it is concluded that T. denticola increases the expression of Aβ1-42 and Aβ1-40 by its regulation onbeta-site amyloid precursor protein cleaving enzyme-1and presenilin1.
Highlights
Alzheimer’s disease (AD), the most common form of dementia, is characterized by a cerebral accumulation and aggregation of amyloid-β (Aβ) peptides and tau hyperphosphorylation, the main components of plaques and tangles respectively (Scheltens et al 2016)
Aβ is a series of short peptides of 38–43 amino acids, produced by degradation of amyloid precursor protein (APP), which is highly expressed in the central nervous system
Our study demonstrated that oral T. denticola infection induces Aβ1−42 and Aβ1−40 accumulation in the hippocampus of C57BL/6 mice by up regulating BACE1 and Presenilin 1 (PS1)
Summary
Alzheimer’s disease (AD), the most common form of dementia, is characterized by a cerebral accumulation and aggregation of amyloid-β (Aβ) peptides and tau hyperphosphorylation, the main components of plaques and tangles respectively (Scheltens et al 2016). Aβ oligomers induce AD-like lesions, such as tau phosphorylation or synaptic loss, and accumulate in brain regions related to memory and cognitive function, resulting in related dysfunction (Viola et al 2015) and recent evidences indicate a role for Aβ as an antimicrobial peptide (Gosztyla et al 2018). Aβ1−42 and Aβ1−40 are the most common toxic subtypes in human body (Wirths et al.2019), which are believed to play a key role in neuronal loss and cognitive dysfunction in AD (Lesné et al 2006). The abnormal expression of BACE1, PS1 and PS2 can affect the cleavage of APP, affecting the production of Aβ
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