Aβ-HMGB1 complex is a pathogenic molecule at the advanced stage of Alzheimer’s disease

Multiple molecules including Aβ, tau and other inflammatory molecules mediate Alzheimer’s disease (AD) pathology. High mobility group box 1 (HMGB1), which is released from necrotic cells and binds to Toll-like receptors (TLRs) of surrounding neurons and microglia, also mediates AD pathology from the early stage. Paradoxically, HMGB1 concentration in cerebrospinal fluid (CSF) at the advanced stage of AD is not higher than that at the early stage. Here we show that Aβ-HMGB1 complexes are generated in neurons undergoing secondary necrosis around Aβ plaques in the AD brain at the advanced stage. Aβ-HMGB1 complex triggers neurite degeneration and necrosis of human normal iPSC-derived neurons via binding to TLR4. Further, two anti-HMGB1 antibodies that inhibit its interaction with TLR4 successfully suppress the toxicity of Aβ-HMGB1 complex to human iPSC-derived neurons, and recover cognitive impairment and Aβ-HMGB1 complex-related brain pathology in AD model mice, while such therapeutic effects were not obvious with an anti-Aβ antibody (lecanemab) approved for human AD patients. Enzyme-Linked Immuno Sorbent Assay (ELISA) revealed plasma level of Aβ-HMGB1 complex was increased in a part of AD patients at the advanced stage. These findings for the molecular basis of toxicity to neurons suggest the significance of Aβ-HMGB1 complex at the advanced stage of AD pathology, and might explain the discrepancy between Aβ burdens and clinical symptoms of human AD patients treated with anti-Aβ antibody.