Beyond Inhibition: Rebalancing the Hsp90 Chaperone Network as a Therapeutic Strategy for Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the pathological accumulation of misfolded amyloid-β (Aβ) and tau, driven by dysfunction of the proteostasis network in which the molecular chaperone heat shock protein 90 (Hsp90) is a central regulator. Here, we propose a shift from pan-inhibition of Hsp90 to rebalancing: selectively normalizing pathological co-chaperone assemblies while preserving homeostatic chaperone functions. We first summarize how specific co-chaperones (eg, FK506-binding protein 51 (FKBP51), activator of Hsp90 ATPase homolog 1 (Aha1), cell division cycle 37(Cdc37)) shift Hsp90 toward tau stabilization, whereas others (eg, C-terminus of Hsc70-interacting protein (CHIP), FK506-binding protein 52 (FKBP52)) promote tau clearance, and we outline Hsp90's context-dependent effects on Aβ. We then trace the evolution of therapeutic strategies from N-terminal ATPase inhibitors, which have shown limited clinical efficacy, to precision approaches including allosteric C-terminal modulators, co-chaperone-selective protein-protein interaction (PPI) inhibitors, induction-based microglial clearance strategies, and epichaperome disruptors. We conclude by critically discussing translational challenges, including blood-brain barrier (BBB) penetration, isoform selectivity, biomarker development, and long-term safety, noting that most current evidence remains preclinical. Rebalancing the Hsp90 chaperone network, rather than inhibiting it indiscriminately, offers a mechanistically grounded yet experimentally early avenue to disease-modifying therapy for AD.