Modulation of gene expression and cytoskeletal dynamics by the amyloid precursor protein intracellular domain (AICD).
Amyloidogenic processing of the amyloid precursor protein (APP) results in the generation of beta-amyloid, the main constituent of Alzheimer plaques, and the APP intracellular domain (AICD). Recently, it has been demonstrated that AICD has transactivation potential; however, the targets of AICD-dependent gene regulation and hence the physiological role of AICD remain largely unknown. We analyzed transcriptome changes during AICD-dependent gene regulation by using a human neural cell culture system inducible for expression of AICD, its coactivator FE65, or the combination of both. Induction of AICD was associated with increased expression of genes with known function in the organization and dynamics of the actin cytoskeleton, including alpha2-Actin and Transgelin (SM22). AICD target genes were also found to be differentially regulated in the frontal cortex of Alzheimer's disease patients compared with controls as well as in AICD/FE65 transiently transfected murine cortical neurons. Confocal image analysis of neural cells and cortical neurons expressing both AICD and FE65 confirmed pronounced changes in the organization of the actin cytoskeleton, including the destabilization of actin fibers and clumping of actin at the sites of cellular outgrowth. Our data point to a role of AICD in developmental and injury-related cytoskeletal dynamics in the nervous system.
Müller
Thorsten
T
Institute of Pathology and Neuropathology, University Hospital Essen, D-45122 Essen, Germany. thorsten.t.mueller@rub.de
Concannon
Caoimhin G
CG
Ward
Manus W
MW
Walsh
Ciara M
CM
Tirniceriu
Anca L
AL
Tribl
Florian
F
Kögel
Donat
D
Prehn
Jochen H M
JH
Egensperger
Rupert
R
D000199:Actins / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology / Q000473:pathology; D003599:Cytoskeleton / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000473:pathology; D017434:Protein Structure, Tertiary; D014162:Transfection
D000199:Actins; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins