Targeting a Master Innate Immune Adaptor Molecule in Alzheimer’s Disease

Mounting evidence indicates key roles for the immune system in Alzheimer’s disease (AD). While recent advancements have been made in identifying cell surface immune receptors that influence AD progression, we still lack knowledge of the intracellular messengers used by these receptors to instruct immune responses in Alzheimer’s disease. Identifying these intracellular signaling molecules is important, as targeting of shared signaling messengers may prove more effective than modulating individual receptors in isolation. Our preliminary studies have identified a novel intracellular signaling pathway that is centrally involved in the disposal of neurotoxic agents from the brain; we have shown that genetic deletion of this messenger results in worsened neurodegenerative disease. These findings suggest that therapeutics that activate this immune signaling pathway may offer novel strategies to treat Alzheimer’s disease. In the proposed studies, we will further reveal how this intracellular immune messenger functions to limit the spread of damaging amyloid beta aggregates in the brain, and also explore a novel role for it in tauopathy. In addition, we will assess the therapeutic efficacy of activating this immune pathway to limit AD pathogenesis.