Freude KK, Penjwini M, Davis JL, Laferla FM, Blurton-Jones M.
Soluble amyloid precursor protein induces rapid neural differentiation of human embryonic stem cells.
J Biol Chem. 2011 Jul 8;286(27):24264-74.
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This paper presents two interesting findings. One is that expression of APP in human embryonic stem cells (hESCs) robustly promotes neuronal differentiation. The other is that this effect is mediated by soluble APP (sAPP) and that sAPPβ is more potent than sAPPα. The data are convincing because the authors obtained consistent results by expressing both the wild-type and the Swedish mutant forms of APP, and in two hESC lines, although it would have been more compelling if they had used controls that are vector-infected and selected under the same procedures as the APP-overexpressing lines. The fact that a twofold overexpression of APP over the endogenous level can drive such strong effects in hESCs is intriguing, especially in light of the work by the De Strooper group showing that mouse ES cells deficient in all APP genes (APP, APLP1, and APLP2) display normal differentiation characteristics under a standard neuronal differentiation protocol (Bergmans et al., 2010). Importantly, how soluble APP mediates these effects remains to be established. This is a critical question for understanding not only the role of APP in stem cell differentiation, but also APP biology in general.
Bergmans BA, Shariati SA, Habets RL, Verstreken P, Schoonjans L, Müller U, Dotti CG, De Strooper B.
Neurons generated from APP/APLP1/APLP2 triple knockout embryonic stem cells behave normally in vitro and in vivo: lack of evidence for a cell autonomous role of the amyloid precursor protein in neuronal differentiation.
Stem Cells. 2010 Mar 31;28(3):399-406.
This paper shows that human embryonic stem (hES) cells overexpressing amyloid precursor protein (APP) display a robust differentiation towards a neural fate. APP-overexpressing H9 and HUES7 hES cells behaved similarly.
Soluble APP fragments (sAPP) were shown to be responsible for this effect, since recombinant sAPPα or sAPPβ treatment of human embryonic stem cells results in the same effect, with APPsβ being the more effective of the two. Both sAPP secreted forms likely act on the same receptor to elicit differentiation, such that the difference between these two secreted APP forms may be due to their differential binding to the same surface receptors. Will the differential effects of sAPPα and sAPPβ on stem cell differentiation still be present for fully post-translationally modified APPs?
As stated by the authors, it is difficult to compare the study performed by Bergmans and colleagues (Bergmans et al., 2010) and the current study. Bergmans et al. used retinoic acid to induce differentiation of mouse APP/APLP1/APLP2 triple knockout ES cells and showed that APP family member deficiency does not prevent stem cell differentiation to the neural fate.
This study suggests that APP family members are not essential for neural differentiation, and that both sAPPs and retinoic acid converge on the same differentiation pathway. If so, then excess sAPP may prevent the maintenance of an undifferentiated state that is dominant over neural fate differentiation under these culture conditions. Is this effect specific to sAPPs, or will recombinant sAPLPα and β produce the same effects?