The Amyloid Precursor Protein Intracellular Domain-Fe65 Multiprotein Complexes: A Challenge to the Amyloid Hypothesis for Alzheimer's Disease?

Figure 1

APP processing pathways involved in the activation and release of the AICD-associated complexes from the plasma membrane. Fe65 is in an autoinhibited conformation in the cytoplasm. The binding to the AICD triggers the exposure of Fe65 WW and PTB1 domains. These protein-protein domains elicit the recruitment to the subcortical domains of the plasma membrane of both c-Abl and Tip60. At the plasma membrane, c-Abl can phosphorylate and activate the protein kinase CDK-5 at Tyr15, and in turn, activated CDK-5 may phosphorylate Ser90 of Tip60. DNA damage or other unknown stimuli may then induce the release of the complex from the membrane through two complementary mechanisms: either by the activation of the γ-secretase or by JNK-dependent phosphorylation of Thr668 in the AICD. In spite of the preferred mechanisms involving the release of the Fe65-complex, it can be translocated to the nucleus where it activates transcription of target genes and is essential in the repair of the DNA double strand-breaks (DSB).