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The Functional Roles of APP Cytoplasmic Domain—Conflicts and Consensus
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The amyloid-β-yielding extracellular domain of APP has gotten most of the attention over the last decade or so, but inside the cell there is a large cytoplasmic fragment that might be the key to understanding the true nature of APP.
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Sanjay Pimplikar led this live discussion on 3 October 2006. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
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 View Transcript of Live Discussion — Posted 21 December 2006
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By Sanjay W. Pimplikar
The amyloid-β precursor protein (APP) cytoplasmic domain exists in three forms—as a part of uncleaved APP, as a part of the membrane-associated C-terminal fragments, and as a free, soluble fragment termed the APP intracellular domain (AICD). Though the cytoplasmic domain has lived in relative obscurity compared to its better-known half, the Aβ peptide, interest in the domain has been aroused by recent reports that addressed its biological roles. The APP cytoplasmic domain interacts with Fe65 (1), along with several other proteins, and the significance of this domain (and that of its interaction with Fe65) was revealed when APP double or triple (APP, APLP1, and APLP2) knockout mice (2) were found to have a similar phenotype as the Fe65 double knockout animals (3). Fe65 associates with both intact APP and free AICD, and the exact mechanism underlying cortical dysplasia seen in these knockout animals poses an exciting challenge in the field.
The APP cytoplasmic domain attracted immense attention with the observations that AICD regulates gene expression (4, 5, and ARF related news story), and a number of studies have since come to similar conclusions. Because it has been difficult to identify the gene targets of AICD, and a recent study has cast doubts about its transcriptional role (6), the debate over AICD’s role in transcriptional regulation is likely to continue in the near future. However, the biological effects of the APP cytoplasmic domain and/or its proteolytic fragments are less uncertain. The observation that a point mutation in the APP cytoplasmic tail (that potentially abolishes the generation of C31 fragment by caspases) rescues memory deficits (7 and ARF related news story) in a mouse model of AD is a significant observation that should prompt re-evaluation of how we look at the etiology of the disease.
It is likely that the APP cytoplasmic domain exerts biological effects as a part of APP-CTFs (such as C99 and C83), although this area of research remains less studied. Another area of interest is the role of phosphorylation of the APP cytoplasmic domain on the T668 residue, its effect on AICD-mediated transcription, and its association with interacting proteins such as Fe65, Dab1, and x11-α. Two recent papers studied the role of T668 phosphorylation and came to opposite conclusions regarding nuclear translocation of AICD and its role in transcription (8,9). In summary, as with other areas of AD research, the studies on APP cytoplasmic domain have generated conflicting and sometimes contradictory views.
The aim of this live discussion is to bring researchers together to discuss the issues related to the APP cytoplasmic domain as a prelude to a mini-symposium on the same topic at the forthcoming SfN meeting in Atlanta (Tuesday, October 18, 8:30 a.m.). Some of the items up for discussion will include the following:
- Does AICD play a role in gene expression? If so, how?
- What is the role of the APP cytoplasmic domain and Fe65 in cortical dysplasia or neuronal migration?
- How does phosphorylation of T668 regulate APP function? What role does Pin1 play, since it binds to the phosphorylated form of APP?
- How does a mutation in the APP cytoplasmic domain (D664A) reduce the memory deficits in a mouse model of AD?
References:
1. Zambrano N, Buxbaum JD, Minopoli G, Fiore F, de Candia P, De Renzis S, Faraonio R, Sabo S, Cheetham J, Sudol M, Russo T. Interaction of the phosphotyrosine interaction/phosphotyrosine binding-related domains of Fe65 with wild-type and mutant Alzheimer's β-amyloid precursor proteins. J Biol Chem. 1997 Mar 7;272(10):6399-405. Abstract
2. Herms J, Anliker B, Heber S, Ring S, Fuhrmann M, Kretzschmar H, Sisodia S, Müller U. Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members. EMBO J. 2004 Oct 13;23(20):4106-15. Abstract
3. Guénette S, Chang Y, Hiesberger T, Richardson JA, Eckman CB, Eckman EA, Hammer RE, Herz J. Essential roles for the Fe65 amyloid precursor protein-interacting proteins in brain development. EMBO J. 2006 Jan 25;25(2):420-31. Abstract
4. Cao X, Südhof TC. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science. 2001 Jul 6;293(5527):115-20. Abstract
5. Gao Y, Pimplikar SW. The gamma -secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus. Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):14979-84. Abstract
6. Hébert SS, Serneels L, Tolia A, Craessaerts K, Derks C, Filippov MA, Müller U, De Strooper B. Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genes. EMBO Rep. 2006 Jul ;7(7):739-45. Abstract
7. Galvan V, Gorostiza OF, Banwait S, Ataie M, Logvinova AV, Sitaraman S, Carlson E, Sagi SA, Chevallier N, Jin K, Greenberg DA, Bredesen DE. Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc Natl Acad Sci U S A. 2006 May 2;103(18):7130-5. Abstract
8. Nakaya T, Suzuki T. Role of APP phosphorylation in Fe65-dependent gene transactivation mediated by AICD. Genes Cells. 2006 Jun ;11(6):633-45. Abstract
9. Chang KA, Kim HS, Ha TY, Ha JW, Shin KY, Jeong YH, Lee JP, Park CH, Kim S, Baik TK, Suh YH. Phosphorylation of amyloid precursor protein (APP) at Thr668 regulates the nuclear translocation of the APP intracellular domain and induces neurodegeneration. Mol Cell Biol. 2006 Jun ;26(11):4327-38. Abstract
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