Toll-like receptor 9 contributes in microglial activation and lysosomal dysfunction to promote Alzheimer’s disease

Toll like receptor 9 (TLR9) is an endosomal-lysosomal innate immune receptor which recognizes microbial and host-derived double-stranded DNA (dsDNA) to induce cellular immunity. TLR9 pathway has been implicated in Alzheimer’s disease (AD) pathology via its ability to modulate peripheral immune cells but its exact role in the central nervous system (CNS) remains unclear. Here we show that extranuclear dsDNA accumulating in human AD brain and in a mouse model of AD, together with microglia around amyloid-β (Aβ) plaques stimulates TLR9 in vitro . Loss of TLR9 inhibits the transition of homeostatic microglia to reactive microglia, a cell type associated with a chronic pro-inflammatory state, promoting their reprogramming into an anti-inflammatory state, thereby restoring lysosomal integrity required for Aβ peptides degradation. Predisposition to lysosome permeabilization could be mimicked with repeated TLR9 stimulation using CpG-A ODNs in a human microglial cell line and was rescued with TLR9 inhibition. Furthermore, lack of TLR9 protects mice developing AD from cognitive defects and neuronal loss. Aβ pathology is also reduced specifically in male mice. Altogether, our results have identified a critical role of TLR9 in AD, where it modulates microglial activation and lysosome function to interfere with the progression of AD. These findings suggest that targeting TLR9 signaling and lysosomal function may be a relevant strategic approach to reduce AD pathology.