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

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.