Intracellular amyloid hypothesis for ultra‐early phase pathology of Alzheimer's disease

Using 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 disease pathology than previously expected. The necrosis is induced by intracellular amyloid accumulation that deprives a critical effector molecule, Yes‐associated protein (YAP), in the Hippo signaling pathway that is essential for cell survival, similarly to TRIAD necrosis observed in transcriptional repression and in other neurodegenerative diseases such as Huntington's disease. The initial TRIAD necrosis due to the intracellular amyloid releases HMGB1 into extracellular space and induces cluster of secondary necrosis around the primary necrotic neurons. Finally, the cluster grows into extracellular amyloid plaque. Inhibition of HMGB1 by anti‐HMGB1 antibody prevents expansion of neurodegeneration. Administration even after onset significantly ameliorates the cognitive decline of Alzheimer's disease model mice. Our results present a new theory of Alzheimer's disease pathology, which can be referred to as the “intracellular amyloid hypothesis".