Treponema pallidum Impairs Microglial Aβ1-42 Clearance by Hijacking TLR2/PI3K/AKT Immune Signaling.

Neurosyphilis sharespathological features with neurodegenerative diseases, notably amyloid-β(Aβ) deposition. Given this association, we sought to elucidate how Treponemapallidum (Tp) mediates Aβ pathology by examining its effects onboth Aβ production and clearance using the integrated invivorabbit model and in vitro systems.Rabbits subjected to intracisternal Tp for two months exhibited elevatedAβ levels in the hippocampus relative to PBS controls. Focusing on the highlyamyloidogenic Aβ1-42 variant, we found that Tpexposure increased Aβ1-42secretion in iPSC-derived neurons byupregulating theexpression of β-site amyloid precursor proteincleaving enzyme 1 without altering amyloid precursor protein levels.Concurrently, impairedmicroglial function in HMC3 cells, markedly inhibiting both phagocytosis anddegradationof Aβ1-42, is quantified by flow cytometry and immunofluorescence. Mechanistic studies revealed that Tpactivates the TLR2/PI3K/AKT signaling pathway, which in turn impairedmicroglial Aβ uptake and clearance, a conclusion robustly supported by our finding thatpharmacological inhibition of this pathway restores clearance function.Our results establish adual mechanism whereby Tp promotes Aβ1-42 accumulation throughcoordinated enhancement of neuronal production and impairment of microglialclearance, an effect mediated via TLR2/PI3K/AKT activation, providing a crucialmechanistic insight into neurosyphilis-associated neurodegeneration.