Journal
NEUROBIOLOGY OF AGING
Volume 31, Issue 1, Pages 58-73Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2008.03.001
Keywords
AICD; NICD; Transcription; Nuclear signaling; Live cell imaging; Tip60; Fe65; Nuclear bodies; FISH
Categories
Funding
- Transregio SFB [6027]
- SNF NCCR
- EU [LSHM-CT-2003-503330]
- Alzheimer's Association
- NIA/National Institutes of Health
- NATIONAL INSTITUTE ON AGING [R01AG018379, R01AG018884] Funding Source: NIH RePORTER
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The beta-amyloid precursor protein (APP) plays a major role in Alzheimer's disease. The APP intracellular domain (AICD), together with Fe65 and Tip60, localizes to spherical nuclear AFT complexes, which may represent sites of transcription. Despite a lack of co-localization with several described nuclear compartments, we have identified a close apposition between AFT complexes and splicing speckles, Cajal bodies and PML bodies. Live imaging revealed that AFT complexes were highly mobile within nuclei and following pharmacological inhibition of transcription fused into larger assemblies. We have previously shown that AICD regulates the expression of its own precursor APP. In support of our earlier findings, transfection of APP promoter plasmids as substrates resulted in cytosolic AFT complex formation at labeled APP promoter plasmids. In addition, identification of chromosomal APP or KA11 gene loci by fluorescence in situ hybridization showed their close association with nuclear AFT complexes. The transcriptional activator Notch intracellular domain (NICD) localized to the same nuclear spots as occupied by AFT complexes suggesting that these nuclear compartments correspond to transcription factories. Fe65 and Tip60 also co-localized with APP in the neurites of primary neurons. Pre-assembled AFT complexes may serve to assist fast nuclear signaling upon endoproteolytic APP cleavage. (C) 2008 Elsevier Inc. All rights reserved.
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