Paper
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Deyts C, Vetrivel KS, Das S, Shepherd YM, Dupré DJ, Thinakaran G, Parent AT. Novel GαS-protein signaling associated with membrane-tethered amyloid precursor protein intracellular domain. J Neurosci. 2012 Feb 1;32(5):1714-29. PubMed.
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This is an excellent study. Not only is the novel interaction of APP/APLP C-terminal fragments with GαS shown to trigger neurite outgrowth, but also the involvement of cAMP/PKA activation and GSK-3β inhibition is in agreement with published evidence showing a role for these signaling events in neurite formation. The authors provide a thoughtful consideration of the implications of APP-CTF-mediated signaling for normal APP function and Alzheimer's disease therapeutics.
Institut de Pharmacologie Moléculaire et Cellulaire
The paper by Deyts and colleagues is of great interest. It shows that the C-terminal stubs derived from α- and β-secretase cleavages of APP, when accumulating, could alter various signaling pathways involving protein kinase A or GSK-3β kinases, and have functional consequences on neurite growth and dendritic arborization. Although the empirical observation of APP-CTF fragment-linked toxicity has already been documented both in vitro and in vivo, the present work’s "added value" stands in the delineation of downstream cascades underlying this toxicity, and, noticeably, by the demonstration that an identified sequence domain located within the sequence of the APP intracellular domain (AICD) could interact with a heterotrimeric G protein subunit.
Another interesting aspect of the paper is the demonstration that the above-described phenotype could be mimicked by an AICD-based construct in which extracellular and transmembrane domains of APP have been replaced by a MyrPalm domain of the Lyn kinase. This is interesting, but also raises some questions. AICD is theoretically released from α- and β-secretase-derived CTF stubs. Therefore, there exists an equilibrium between CTF stubs and their proteolytic fragment AICD that is tightly regulated. Most of the work examines the consequences of overexpressing CTF or an artificial AICD construct tethered to the membrane, but does not really establish whether endogenous CTF or AICD could interfere with PKA or GSK-3β pathways. This would be particularly important with respect to the fact that α-CTF-derived AICD appears to be very short lived and undergoes rapid cytosolic degradation, while β-CTF-derived AICD appears to be produced in the endocytic pathway that protects it from exacerbated degradation. The β path allows AICD to signal to the nucleus where it can modulate gene transcription (for a review, see 1). Therefore, the source of endogenous AICDs, i.e., derived from α-CTF or β-CTF stubs, and their respective abilities to modulate PKA and GSK-3β pathways, could better help us understand which of the fragments, besides Aβ or Aβ-related species, can contribute to neuronal morphological alterations.
It remains that the paper by Deyts and colleagues unravels a dual mechanism by which membrane-embedded APP-CTF and APP-CTF-derived AICD could, in a complementary manner, trigger deleterious effects via distinct cellular pathways in neuronal cells.
References:
Pardossi-Piquard R, Checler F. The physiology of the β-amyloid precursor protein intracellular domain AICD. J Neurochem. 2012 Jan;120 Suppl 1:109-24. PubMed.
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