Neuroinvasion pathways of Treponema denticola and its role in amyloidogenesis and neuroinflammation: A systematic review.

Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by the accumulation of amyloid-β (Aβ) plaques, tau hyperphosphorylation, and persistent neuroinflammation. Emerging research indicates that Treponema denticola (T. denticola), a prominent periodontal pathogen, plays a role in AD development through various neuroinvasive mechanisms. This systematic review synthesizes current evidence regarding T. denticola ability to penetrate the central nervous system via trigeminal and hematogenous routes, disrupt the blood-brain barrier, and create enduring biofilms within neural tissues. The pathogen's virulence factors, including dentilisin, lipooligosaccharides (LOS), and major surface proteins, trigger β-secretase (BACE1) and mitogen-activated protein kinase (MAPK/JNK) pathways. These processes contribute to increased Aβ production, tau phosphorylation, and neuronal apoptosis. Furthermore, T. denticola-driven activation of microglia and astrocytes intensifies neuroinflammatory responses involving IL-1β, TNF-α, and IL-6, leading to synaptic dysfunction and cognitive impairment. Studies on murine models reveal that prolonged oral infection with T. denticola induces Alzheimer's-like neuropathological changes, such as hippocampal Aβ accumulation and neuron loss. Taken together, these insights emphasize the impact of periodontal pathogens as modifiable risk factors in AD progression and underscore the necessity of further longitudinal and interventional research to clarify causal pathways and therapeutic possibilities. Incorporating targeted antimicrobial approaches and effective periodontal care may provide innovative strategies for reducing AD progression risks.