期刊
JOURNAL OF CELL SCIENCE
卷 122, 期 20, 页码 3703-3714出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.048090
关键词
AICD; Amyloid precursor protein; Endocytosis; Nuclear signaling; Retrograde transport
类别
资金
- Transregio SFB (6027) on Structure and Function of Membrane Proteins
- SNF NCCR on Neural Plasticity and Repair
- EU [LSHM-CT-2003-503330]
- Alzheimer Forschung Initiative
Proteolytic processing of the amyloid precursor protein (APP) occurs via two alternative pathways, localized to different subcellular compartments, which result in functionally distinct outcomes. Cleavage by a beta-gamma sequence generates the A beta peptide that plays a central role in Alzheimer's disease. In the case of beta-gamma cleavage, a secreted neurotrophic molecule is generated and the A beta peptide cleaved and destroyed. In both cases, a cytosolic APP intracellular domain (AICD) is generated. We have previously shown that coexpression of APP with the APP-binding protein Fe65 and the histone acetyltransferase Tip60 results in the formation of nuclear complexes (termed AFT complexes), which localize to transcription sites. We now show that blocking endocytosis or the pharmacological or genetic inhibition of the endosomal beta-cleavage pathway reduces translocation of AICD to these nuclear AFT complexes. AICD signaling further depends on active transport along microtubules and can be modulated by interference with both anterograde and retrograde transport systems. Nuclear signaling by endogenous AICD in primary neurons could similarly be blocked by inhibiting beta-cleavage but not by alpha-cleavage inhibition. This suggests that amyloidogenic cleavage, despite representing the minor cleavage pathway of APP, is predominantly responsible for AICD-mediated nuclear signaling.
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