The amyloid precursor protein was first cloned in 1987. Twenty years and 4,000+ papers later, the function of APP is still shrouded in mystery, despite the overwhelming weight of evidence linking the precursor protein to Alzheimer disease. Is the field getting any closer to pinning down a physiological role for APP? Is it involved in membrane trafficking, cell signaling, calcium homeostasis? Theories abound, but which hold most water?
The purpose of the live discussion was to review some of the latest research on APP and try to build a consensus on its physiological function. It also provided a sneak preview of a similarly focused symposium at this year’s Society for Neuroscience meeting in San Diego, California. View details on this symposium. For more on this live discussion, see background text below.
Sanjay W. Pimplikar and Suzanne Guenette led this live discussion on 11 October 2007. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
By Sanjay W. Pimplikar
The cloning of amyloid precursor protein (APP) was reported in 1987, and since then this protein has been a focus of intense study due to its role in generating Aβ. APP is expressed ubiquitously. Early functional information on its role was obtained from in vitro studies on neuronal and non-neuronal tissue culture and cell models. These reports were followed by in vivo studies using animal models that were genetically manipulated to delete or to overexpress APP. Although most in vivo studies utilized the mouse as a model, a number of observations were made in worms, flies, and other rodent systems. As a result, a massive amount of data on the possible function of APP are available, which are reviewed in many excellent recent articles (1-3). Although no definitive function has yet been assigned to APP, recent studies from multiple groups implicate APP in a) larval development and pharyngeal pumping in Caenorhabditis elegans; b) behavioral alterations, axonal transport, dendritic arborization, and neuronal viability in Drosophila; and c) neuromuscular junction formation and neuronal positioning in the developing cortex, and axon outgrowth in mice. In addition, APP has been implicated in cell signaling, gene expression, calcium homeostasis, and membrane trafficking, and this list is likely to be incomplete since APP has been associated with many cellular processes. An ancillary symposium related to this subject matter and entitled "Function of APP Gene Family Members and Clues to AD Pathogenesis: Studies from Worms to Mammals" will be held at the Annual Meeting of the Society for Neuroscience, San Diego on Sunday, 4 November 2007 at 6:30-9:30 p.m.
The primary aim of this live discussion is to invite experts (and interested researchers) in the field to discuss the rather vast amount of data and see if a consensus can be reached about APP's normal physiological function or functions. Although we know how APP deletion or overexpression affects a given experimental parameter, it has proved difficult to translate this knowledge into a definitive framework that brings us closer to its normal physiological function in humans. With this central goal in mind, we plan to discuss and deliberate the available data in three parts:
1. What are the different functional roles ascribed to APP in vitro and in animal systems? As pointed out above, APP has been implicated in a number of functions. Are the data consistent or are there anomalies? Does APP perform a different function in non-neuronal cells? Does AICD really regulate the transcription? If so, how?
2. Is there a common cellular or molecular mechanism that underlies the observed phenomena? This issue has not been addressed systematically. At first glance, APP seems like the “Jack of All Trades,” which performs a wide array of cellular activities. Is there a common unifying mechanism that could connect such diverse functions as formation of neuromuscular junctions, membrane trafficking, behavioral alterations, and postnatal lethality?
3. Finally, if we recognize a unifying cellular function of APP, will it give us a better insight into the pathogenesis of Alzheimer disease? The present attempts to understand the etiology of the disease are focused on the Aβ peptide as a potential proximal agent of pathogenesis. Since APP processing is invariably coupled to APP function, can elucidation of the normal function of APP (and hence the biological necessity of APP processing) lead to a more precise mechanism of AD pathogenesis?
1. Zheng H, Koo EH. The amyloid precursor protein: beyond amyloid. Mol Neurodegener. 2006 Jul 3;1:5. Abstract
2. Senechal Y, Larmet Y, Dev KK. Unraveling in vivo functions of amyloid precursor protein: insights from knockout and knockdown studies. Neurodegener Dis. 2006;3(3):134-47. Review. Abstract
3. Wolfe MS, Guenette SY. APP at a glance. J Cell Sci. 2007 Sep 15;120(Pt 18):3157-61. No abstract available. Abstract
- Zheng H, Koo EH. The amyloid precursor protein: beyond amyloid. Mol Neurodegener. 2006;1:5. PubMed.
- Senechal Y, Larmet Y, Dev KK. Unraveling in vivo functions of amyloid precursor protein: insights from knockout and knockdown studies. Neurodegener Dis. 2006;3(3):134-47. PubMed.
- Wolfe MS, Guénette SY. APP at a glance. J Cell Sci. 2007 Sep 15;120(Pt 18):3157-61. PubMed.
- Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999 Oct 22;286(5440):735-41. PubMed.