Treponema Denticola Induces Neuronal Apoptosis by Promoting Amyloid-β Deposition in Mice

Objectives: Chronic periodontitis has been identified as an important risk factor for Alzheimer’s disease (AD). Our previous studies found that oral infections of periodontal pathogens, Treponema denticola (T. denticola) could result in brain colonization and induction of AD pathology, such as an increase in Aβ burden, tau hyperphosphorylation, and neuroinflammation in the hippocampi of mice. This study aims to investigate the roles of T. denticola on the neuronal apoptosis in the hippocampi by using an oral infection mouse model.
Methods: An oral infection mouse model was constructed via oral administration of T. denticola (10⁹ CFU/mL/50 µL) for 24 weeks at a frequency of three times per week. Neuronal apoptosis rate in mouse hippocampi was assessed by TUNEL staining. The expression levels of apoptotic associated genes and proteins including BCL-W, SAPK/JNK and SMAC were assessed using qRT-PCR and western blot. N2a neuronal cells were co-incubated with T. denticola (multiplicity of infection (MOI) 1:100), Aβ_1-40, Aβ_1-42, and Aβ inhibitor KMI1303 to verify the underlying mechanism.
Results: T. denticola induced neuronal apoptosis in the mouse hippocampus, the mRNA and protein expression levels of cleaved caspase-3, SAPK/JNK and SMAC were up-regulated in the T. denticola infection group, while the level of BCL-W was significantly down-regulated. N2a cells treated with Aβ_1-42 and T. denticola showed increased rates of apoptosis, increased expression of cleaved caspase-3, SAPK/JNK, and SMAC proteins, and decreased expression of BCL-W. Moreover, an Aβ inhibitor KMI1303 reversed the pro-apoptotic effects of T. denticola on N2a cells.
Conclusions: T. denticola oral infection could induce neuronal apoptosis in mice. The potential mechanism might be related to the intrinsic mitochondrial pathway mediated by Aβ.