| First Author | Ludewig S | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 26 | PubMed ID | 34172567 |
| Mgi Jnum | J:307211 | Mgi Id | MGI:6719464 |
| Doi | 10.1073/pnas.2011506118 | Citation | Ludewig S, et al. (2021) APPsalpha rescues impaired Ca(2+) homeostasis in APP- and APLP2-deficient hippocampal neurons. Proc Natl Acad Sci U S A 118(26):e2011506118 |
| abstractText | Alterations in Ca(2+) 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-beta-mediated functions on neuronal Ca(2+) 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(2+) handling and identify especially the ectodomain APPsalpha as an essential regulator of Ca(2+) homeostasis. Importantly, we demonstrate that the loss of APP and APLP2, but not APLP2 alone, impairs Ca(2+) handling, the refill of the endoplasmic reticulum Ca(2+) stores, and synaptic plasticity due to altered function and expression of the SERCA-ATPase and expression of store-operated Ca(2+) channel-associated proteins Stim1 and Stim2. Long-term AAV-mediated expression of APPsalpha, but not acute application of the recombinant protein, restored physiological Ca(2+) 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 APPsalpha in Ca(2+) homeostasis, thereby highlighting its therapeutic potential. |
