期刊
NEUROPATHOLOGY
卷 41, 期 2, 页码 93-98出版社
WILEY
DOI: 10.1111/neup.12738
关键词
expansion of neurodegeneration; high mobility group box 1 (HMGB1); intracellular amyloid hypothesis; transcriptional repression‐ induced atypical cell death (TRIAD); Yes‐ associated protein (YAP)
This study reveals that neuronal necrosis occurs much earlier in Alzheimer's disease pathology than previously expected, induced by intracellular amyloid accumulation which deprives the critical effector molecule YAP in the Hippo signaling pathway, ultimately leading to neuronal death.
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.
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