Hsp90 co-chaperone degradation combined with antioxidation nanostrategy to rescue tauopathy-induced Alzheimer’s disease

Tau pathology is a major hallmark and potential drug therapeutic target of Alzheimer's disease (AD). Effective clearance of hyperphosphorylated tau protein (p-tau) is very difficult, not only because the intracellular repair defense collapses and degradation fails, but also because the extracellular pathological environment always aggravates its production. Herein, hollow mesoporous prussian blue nanoparticles (HMPB NPs) loaded with a high-affinity Hsp90 inhibitor 17-AAG are constructed as HMPB-AAG nanoagents for the combined rescue of tauopathy-induced AD. In this nanoagent, 17-AAG achieves Hsp90 co-chaperone degradation of p-tau and HMPB NPs exert antioxidation property. In vitro and in vivo studies reveal that HMPB-AAG nanoagents can produce a combinational therapeutic effect on tau-related pathology by reducing p-tau levels, alleviating oxidative stress and neuroinflammation, and inhibiting neuronal apoptosis and synaptic damage. Hippocampal stereotaxic microinjections of HMPB-AAG nanoagents into okadaic acid-induced AD-like rats have shown to significantly reverse tauopathy-induced cognitive impairment. Overall, this work takes advantage of the combination of intracellular and extracellular regulatory strategies targeting tau hyperphosphorylation, providing a promising and efficient therapeutic candidate agent for AD and other tau-related neurodegenerative diseases.