A Dual-Layer Microglial framework for Alz heimer's Disease: Inflammatory Reset via STING Inhibition and Functional Reprogram ming via OLE

Alzheimer’s disease (AD) is increasingly recognized as a disorder involving not only amyloid-β (Aβ) and tau pathology but also profound neuroimmune dysregulation. Microglia, the resident immune cells of the central nervous system, progressively transition from protective homeostatic states toward chronically activated phenotypes characterized by excessive inflammation, impaired plaque containment, and neuronal injury. Two emerging therapeutic strategies target complementary aspects of this dysfunction: pharmacological inhibition of the cGAS-STING innate immune pathway and OLE-mediated microglial reprogramming through the PM20D1 pathway. STING inhibition reduces pathological type I interferon signaling and chronic neuroinflammation, whereas OLE (N-oleoyl-leucine) enhances cellular metabolism and promotes protective microglial functions. This article proposes a dual-layer therapeutic framework in which STING inhibition acts as an initial inflammatory reset, creating a permissive environment for subsequent OLE-driven functional reprogramming. Although the combined approach remains untested experimentally, its complementary mechanisms suggest a promising strategy for restoring microglial homeostasis and slowing Alzheimer’s disease progression.