The CHIP-LMO7-BAG5 complex controls tau clearance and yields repurposed and newly designed therapeutic candidates for Alzheimer's disease

Abstract

Through cross-species genetic screens, we identified LMO7 as a regulator of tau levels in vivo. LMO7 bridges the E3 ligase CHIP and its inhibitory cochaperone BAG5, suppressing CHIPs ligase activity and limiting tau ubiquitination and degradation. Adult LMO7 knockdown enhances CHIP activity, reduces total and phosphorylated tau, attenuates gliosis, and rescues memory deficits in tauopathy mice. Guided by AlphaFold-derived structural models and AI-based virtual screening, we developed a CHIP-derived competing peptide and identified FDA-approved drugs that disrupt the complex. Viral delivery of the peptide or oral administration of Telmisartan or MPA-2, an optimized Mycophenolic acid derivative, reduced pathogenic tau without toxicity. These findings establish CHIP-LMO7-BAG5 complex as a druggable node in tau homeostasis, with implications for tauopathies including Alzheimers disease, and STUB1-associated ataxias.