APP binds DR6 to trigger axon pruning and neuron death via distinct caspases

Article

关键词: AMYLOID PRECURSOR PROTEIN;    PROGRAMMED CELL-DEATH;    BAX-DEFICIENT MICE;    ALZHEIMERS-DISEASE;    NERVOUS-SYSTEM;    COMMISSURAL AXONS;    GENE-EXPRESSION;    FAMILY-MEMBERS;    TNF RECEPTOR;    DEGENERATION;   

DOI  :  10.1038/nature07767

来源: SCIE

【 摘 要 】

Naturally occurring axonal pruning and neuronal cell death help to sculpt neuronal connections during development, but their mechanistic basis remains poorly understood. Here we report that beta-amyloid precursor protein ( APP) and death receptor 6 ( DR6, also known as TNFRSF21) activate a widespread caspase- dependent self- destruction program. DR6 is broadly expressed by developing neurons, and is required for normal cell body death and axonal pruning both in vivo and after trophic- factor deprivation in vitro. Unlike neuronal cell body apoptosis, which requires caspase 3, we show that axonal degeneration requires caspase 6, which is activated in a punctate pattern that parallels the pattern of axonal fragmentation. DR6 is activated locally by an inactive surface ligand( s) that is released in an active form after trophic- factor deprivation, and we identify APP as a DR6 ligand. Trophic- factor deprivation triggers the shedding of surface APP in a beta-secretase ( BACE)- dependent manner. Loss- and gain- of- function studies support a model in which a cleaved amino- terminal fragment of APP ( N- APP) binds DR6 and triggers degeneration. Genetic support is provided by a common neuromuscular junction phenotype in mutant mice. Our results indicate that APP and DR6 are components of a neuronal self- destruction pathway, and suggest that an extracellular fragment of APP, acting via DR6 and caspase 6, contributes to Alzheimer's disease.

【 授权许可】

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