<i>Treponema pallidum</i> Impairs Microglial Aβ ₁ _– ₄ ₂ 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 <i>Treponemapallidum</i> (<i>Tp</i>) mediates Aβ pathology by examining its effects onboth Aβ production and clearance using the integrated <i>invivo</i>rabbit model and <i>in vitro</i> systems.Rabbits subjected to intracisternal <i>Tp</i> for two months exhibited elevatedAβ levels in the hippocampus relative to PBS controls. Focusing on the highlyamyloidogenic Aβ_1-42 variant, we found that <i>Tp</i>exposure increased Aβ_1-42secretion 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 Aβ_1-42, is quantified by flow cytometry and immunofluorescence. Mechanistic studies revealed that <i>Tp</i>activates 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 <i>Tp</i> promotes Aβ_1-42 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.