APPsα rescues impaired Ca homeostasis in APP- and APLP2-deficient hippocampal neurons.

Alterations in Ca 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 Ca 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 Ca handling and identify especially the ectodomain APPsα as an essential regulator of Ca homeostasis. Importantly, we demonstrate that the loss of APP and APLP2, but not APLP2 alone, impairs Ca handling, the refill of the endoplasmic reticulum Ca stores, and synaptic plasticity due to altered function and expression of the SERCA-ATPase and expression of store-operated Ca channel-associated proteins Stim1 and Stim2. Long-term AAV-mediated expression of APPsα, but not acute application of the recombinant protein, restored physiological Ca 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 Ca homeostasis, thereby highlighting its therapeutic potential.