Targeted degradation of RAGE restores microglial homeostasis and rescues cognitive deficits in 3xTg-AD mice

Chronic neuroinflammation and microglial dysfunction lie at the core of Alzheimer’s disease (AD) pathogenesis. The Receptor for Advanced Glycation End-products (RAGE) serves as a pivotal upstream driver of this inflammatory cascade and associated oxidative stress. However, conventional inhibitors have faltered in clinical trials due to dose-limiting toxicities and their inability to abrogate the receptor’s non-ligand scaffolding functions, underscoring the urgent need for novel strategies capable of complete protein clearance. Here, we report the development of a series of RAGE-targeting Proteolysis Targeting Chimeras (PROTACs), identifying compound 18a as a potent lead candidate. We demonstrate that 18a induces RAGE degradation via the ubiquitin-proteasome system in Aβ-stimulated BV2 cells and achieves robust in vivo target clearance in 3xTg-AD mice. Mechanistically, 18a effectively dismantles the RAGE/NF-κB/NLRP3 inflammatory axis and reinvigorates Nrf2-mediated antioxidant signaling, thereby mitigating oxidative stress and arresting mitochondrial apoptosis. Notably, unbiased transcriptomic profiling reveals that 18a treatment reprograms the hippocampal immune microenvironment, driving a phenotypic shift in microglia from a chronic hyperactivated state toward a homeostatic surveillance signature. This restoration of glial homeostasis is concomitant with a significant amelioration of amyloid pathology and synaptic loss, ultimately rescuing cognitive deficits in AD mice. Collectively, our study establishes compound 18a as a pioneering RAGE-targeting PROTAC that severs the vicious cycle of neuroinflammation and oxidative stress, providing compelling proof-of-concept for RAGE degradation as a viable disease-modifying therapeutic strategy for AD. Schematic illustration of the RAGE-targeting PROTAC 18a and its therapeutic mechanism. The novel PROTAC degrader (18a) induces robust proteasomal degradation of RAGE by recruiting E3 ubiquitin ligase. This targeted clearance disrupts the Aβ-RAGE vicious cycle, suppresses the p38 MAPK/NF-κB inflammatory cascade, and activates the Nrf2 antioxidant pathway, ultimately restoring microglial homeostasis and rescuing cognitive deficits in AD