Cleavage of the amyloid precursor protein (APP) within the amyloid‐beta (Aβ) sequence by the α‐secretase prevents the formation of toxic Aβ peptides. It has been shown that the disintegrin‐metalloproteinases ADAM10 and TACE (ADAM17) act as α‐secretases and stimulate the generation of a soluble neuroprotective fragment of APP, APPsα. Here we demonstrate that the related APP‐like protein 2 (APLP2), which has been shown to be essential for development and survival of mice, is also a substrate for both proteinases. Overexpression of either ADAM10 or TACE in HEK293 cells increased the release of neurotrophic soluble APLP2 severalfold. The strongest inhibition of APLP2 shedding in neuroblastoma cells was observed with an ADAM10‐preferring inhibitor. Transgenic mice with neuron‐specific overexpression of ADAM10 showed significantly increased levels of soluble APLP2 and its C‐terminal fragments. To elucidate a possible regulatory mechanism of APLP2 shedding in the neuronal context, we examined retinoic acid‐induced differentiation of neuroblastoma cells. Retinoic acid treatment of two neuroblastoma cell lines upregulated the expression of both APLP2 and ADAM10, thus leading to an increased release of soluble APLP2.