2021 Volume 38 Issue 3 Pages 347-352
By utilizing a new marker of necrosis pSer46–MARCKS, which was identified by comprehensive phosphoproteome analysis as a phosphoprotein changed before appearance of extracellular amyloid aggregation, we discovered that neuronal necrosis occurs much earlier in Alzheimer's disaese pathology than expected. The necrosis is induced by intracellular amyloid accumulation that deprives a critical effector molecule, YAP in Hippo signaling pathway essential for cell survival, similarly to TRIAD necrosis observed in transcriptional repression and in other neurodegenerative disease such as Huntington's disease. The initial TRIAD necrosis due to intracellular amyloid releases HMGB1 to extracellular space and induces a cluster of secondary necrosis around the primary necrotic neurons, and finally the cluster grows to an extracellular amyloid plaque. Inhibition of HMGB1 by anti–HMGB1 antibody prevents expansion of neurodegeneration and administration even after the onset significantly ameliorates the cognitive decline of Alzheimer's disease model mice. Our results present a new scheme of Alzheimer's disease pathology, which can be named as “intracellular amyloid hypothesis”.
