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Role of APP

The precise physiological role (s) of APP is unknown, although recent experiments indicate roles for APP fragments in axonal transport (Kamal et al 2000 cell adhesion, cell survival, cholesterol metabolism, gene transcription and cognitive processes (reviewed by Turner et al 2003

All APP fragments occur under normal physiological conditions and evidence suggests that they have opposing functions, indicating tight control of processing events. Secreted APPs, especially sAPPα, exert neurotrophic and protective effects, which indicate a potential role in learning and memory (reviewed by Turner et al 2003 Conversely, increased Aβ depresses synaptic transmission (Walsh et al 2002 suggesting the existence of a possible negative feedback loop where production of sAPPs and Aβ is tightly regulated to control neuronal plasticity (reviewed by Wilquet and De Strooper 2004 In addition, C-terminal fragments of APP are involved in interactions with many proteins; Fe65 (Cao and Sudhof 2001 X11α (King et al 2003 Numb, JIP1b (Scheinfeld et al 2002 Taru et al 2002 AIDA-1 (Ghersi et al 2004 LRP and the kinesin light chain (Kamal et al 2000 These interactions regulate a variety of cell processes, for example activation of transcription via Fe65 (Cao and Sudhof 2001 2004 Chang et al 2003 activation of JNK signalling pathways via JIP1b (Bodles and Barger 2005 Marques et al 2003 and regulation of axonal transport via binding to the kinesin light chain (Kamal et al 2000 2001 Stokin et al 2005

All proposed functions of APP are regulated by APP processing events. Access of the secretases to its substrate is regulated in a variety of methods and likely in response to cell signals. These processing events are mediated by the binding of other proteins to APP, for example, C-terminal binding substrates (King et al 2004 Chang et al 2003 Ghersi et al 2004 APOE (Irizarry et al 2004 cytokines (Liao et al 2004 and more recently, the binding of F-spondin, the first identified ligand for APP (Ho and Sudhof 2004

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Role of APP