Sex-biased Toll-Like Receptor 7 (TLR7) Signaling in Demyelination and its Inhibition by Small Molecules

Demyelination, or the loss of myelin, naturally occurs with aging but is worsened in several neurodegenerative diseases. Many of these diseases, including Alzheimer’s, show sex differences. However, it is unclear if demyelination in aging or neurodegeneration is sex-biased. Primary drivers of biological sex include gonadal hormones and sex chromosomes, yet the roles of these factors in the demyelination of aging and disease also remain elusive. In a recent study, we have shown that one of the X-linked genes, Toll-like receptor 7 (TLR7), is a key player in mediating tau-induced deficits in a sex-specific manner. We showed that activation or inhibition of TLR7 alters microglial IFN-I responses in a male-specific manner. Moreover, ablation of TLR7 not only eliminates sex differences in microglia responding to demyelination but also sex differences in non-TLR7 expressing cell types such as oligodendrocytes. A small inhibitor of TLR7 protected against demyelination in male tauopathy mice. This raises the possibility that TLR7 may play a more predominant role in the demyelination processes of males than in females, and a TLR7 inhibitor might be more effective in treating demyelination in male than female patients. We propose to extend the study to dissect the differences between human male and female microglia lacking TLR7 and to develop specific TLR7 inhibitors to assess their efficacies against demyelination and other AD-associated pathologies. We propose two goals: (I) To dissect the cell-autonomous and non-autonomous mechanisms underlying the sex differences in TLR7 signaling in demyelination and tau pathology, and (II) To identify and develop novel brain permeable small molecule inhibitors of TLR7 to inhibit myelin loss and inflammation.