ORIGINAL PAPER APLP1 promotes dFoxO-dependent cell death in Drosophila Xingjun Wang • Yeqing Ma • Yu Zhao • Yujun Chen • Yujia Hu • Changyan Chen • Yingyao Shao • Lei Xue Published online: 5 March 2015 Ó Springer Science+Business Media New York 2015 Abstract The amyloid precursor like protein-1 (APLP1) belongs to the amyloid precursor protein family that also includes the amyloid precursor protein (APP) and the amyloid precursor like protein-2 (APLP2). Though the three proteins share similar structures and undergo the same cleavage processing by a-, b- and c-secretases, APLP1 shows divergent subcellular localization from that of APP and APLP2, and thus, may perform distinct roles in vivo. While extensive studies have been focused on APP, which is implicated in the pathogenesis of Alzhei- mer’s disease, the functions of APLP1 remain largely elusive. Here we report that the expression of APLP1 in Drosophila induces cell death and produces developmental defects in wing and thorax. This function of APLP1 de- pends on the transcription factor dFoxO, as the depletion of dFoxO abrogates APLP1-induced cell death and adult de- fects. Consistently, APLP1 up-regulates the transcription of dFoxO target hid and reaper-two well known pro-apoptotic genes. Thus, the present study provides the first in vivo evidence that APLP1 is able to induce cell death, and that FoxO is a crucial downstream mediator of APLP1’s activity. Keywords APLP1 Á dFoxO Á Cell death Á Drosophila Introduction Human amyloid precursor like protein-1 (APLP1) belongs to a protein family which also contains amyloid precursor protein (APP) and amyloid precursor like protein-2 (APLP2) [1–5].The three proteins share similar structures with conserved N- and C-terminal domains, and can be cleaved by the same a-, b- and c-secretases [6–10], im- plying that they might perform similar functions in devel- opment. Previous studies revealed that single knock-out mice of APP, APLP1 or APLP2 produced only subtle phenotypes, while double knock-out APP/APLP2 or APLP1/APLP2 mice died shortly after birth, implying a possible functional redundancy among the proteins [11– 13].However, other studies suggest that these proteins may bear diverse functions rather than simply compensating for each other [14–16]. In particular, APLP1 exhibits distinct expression pattern and subcellular localization from that of APP and APLP2. While APP and APLP2 are ubiquitously expressed and predominantly distributed in intracellular compartments including the endosomes, ER and Golgi apparatus [5], APLP1 specifically concentrates in the ner- vous system but also shows a weak signal in other tissues such as heart, lung, liver and kidney of E15 mouse embryos observed by in situ hybridization [17]. However, the functions of APLP1 in the non-neuronal tissues remain unknown. APLP1 mainly localizes to the plasma mem- brane [5], indicating APLP1 may perform divergent in vivo functions from that of APP and APLP2. Though all APP family members are able to generate the intracellular do- mains (ICDs) through cleavage by c- and e-secretases [18– 22], ICDs derived from APP and APLP2, but not APLP1, Electronic supplementary material The online version of this article (doi:10.1007/s10495-015-1097-1) contains supplementary material, which is available to authorized users. X. Wang Á Y. Ma Á Y. Zhao Á Y. Chen Á Y. Hu Á C. Chen Á Y. Shao Á L. Xue (&) Institute of Intervention Vessel, Shanghai 10th People’s Hospital, Shanghai Key Laboratory of Signaling and Diseases Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China e-mail: lei.xue@tongji.edu.cn X. Wang e-mail: 2011wxj_fly_ing@tongji.edu.cn 123 Apoptosis (2015) 20:778–786 DOI 10.1007/s10495-015-1097-1