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APPsα rescues impaired Ca2+ homeostasis in APP- and APLP2-deficient hippocampal neurons

Significance Ca2+ dysfunction is correlated to the progression of Alzheimer’s disease; mechanistic insight into the physiological role of the amyloid precursor protein (APP) for Ca2+ homeostasis is still missing. We demonstrate that loss of APP and its homolog APLP2, but not APLP2 alone, impairs Ca2+ handling and synaptic plasticity because of altered function of endoplasmic reticulum Ca2+ stores caused by altered expression and function of the SERCA-ATPase as well as by expression of store-operated Ca2+ channel–associated proteins Stim1 and Stim2. Long-term expression of the APPsα ectodomain restored physiological Ca2+ homeostasis, protein expression, and synaptic plasticity in APP/APLP2 cDKO cultures, emphasizing the role of the APP family and especially of the ectodomain APPsα in Ca2+ homeostasis, thereby highlighting its therapeutic potential. Alterations in Ca2+ homeostasis have been reported in several in vitro and in vivo studies using mice expressing the Alzheimer’s disease–associated transgenes, presenilin and the amyloid precursor protein (APP). While intense research focused on amyloid-β–mediated functions on neuronal Ca2+ handling, the physiological role of APP and its close homolog APLP2 is still not fully clarified. We now elucidate a mechanism to show how APP and its homolog APLP2 control neuronal Ca2+ handling and identify especially the ectodomain APPsα as an essential regulator of Ca2+ homeostasis. Importantly, we demonstrate that the loss of APP and APLP2, but not APLP2 alone, impairs Ca2+ handling, the refill of the endoplasmic reticulum Ca2+ stores, and synaptic plasticity due to altered function and expression of the SERCA-ATPase and expression of store-operated Ca2+ channel–associated proteins Stim1 and Stim2. Long-term AAV-mediated expression of APPsα, but not acute application of the recombinant protein, restored physiological Ca2+ homeostasis and synaptic plasticity in APP/APLP2 cDKO cultures. Overall, our analysis reveals an essential role of the APP family and especially of the ectodomain APPsα in Ca2+ homeostasis, thereby highlighting its therapeutic potential.