A biocompatible photooxygenation catalyst that can selectively oxygenate and degrade the pathogenic aggregation of Alzheimer's disease (AD)-related amyloid-b peptide (Ab) under near-infrared light irradiation has been developed. The catalyst oxygenates Ab embedded under the skin of a living mouse and diminishes the intact Ab level in an AD-model mouse brain. The new catalyst is potentially applicable for the treatment of peripheral amyloid diseases and AD.
Protein degradation induced by small molecules by recruiting endogenous protein degradation systems, such as ubiquitin-proteasome systems, to disease-related proteins is an emerging concept to inhibit the function of undruggable proteins. Protein targets without reliable ligands and/or existing outside the cells where ubiquitin-proteasome systems do not exist, however, are beyond the scope of currently available protein degradation strategies. Here, we disclose photooxygenation catalyst 7 that permeates the blood-brain barrier and selectively and directly degrades an extracellular Alzheimer’s disease–related undruggable protein, amyloid-β protein (Aβ). Key was the identification of a compact but orange color visible light–activatable chemical catalyst whose activity can be switched on/off according to its molecular mobility, thereby ensuring high selectivity for aggregated Aβ. Chemical catalyst–promoted protein degradation can be applied universally for attenuating extracellular amyloids and various pathogenic proteins and is thus a new entry to induced protein degradation strategies.
Amyloid-selective catalytic photo-oxygenation of the tau protein is a possible therapeutic strategy for Alzheimer's disease, via the inhibition of tau fibril formation.
Amyloid formation and the deposition of the amyloid-β peptide are hallmarks of Alzheimer’s disease pathogenesis. Immunotherapies using anti-amyloid-β antibodies have been highlighted as a promising approach for the prevention and treatment of Alzheimer’s disease by enhancing microglial clearance of amyloid-β peptide. However, the efficiency of antibody delivery into the brain is limited, and therefore an alternative strategy to facilitate the clearance of brain amyloid is needed. We previously developed an artificial photo-oxygenation system using a low molecular weight catalytic compound. The photocatalyst specifically attached oxygen atoms to amyloids upon irradiation with light, and successfully reduced the neurotoxicity of aggregated amyloid-β via inhibition of amyloid formation. However, the therapeutic effect and mode of actions of the photo-oxygenation system in vivo remained unclear. In this study, we demonstrate that photo-oxygenation facilitates the clearance of aggregated amyloid-β from the brains of living Alzheimer’s disease model mice, and enhances the microglial degradation of amyloid-β peptide. These results suggest that photo-oxygenation may represent a novel anti-amyloid-β strategy in Alzheimer’s disease, which is compatible with immunotherapy.
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