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...
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| Main Authors: | , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
June 25, 2021
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| In: |
Proceedings of the National Academy of Sciences of the United States of America
Year: 2021, Volume: 118, Issue: 26, Pages: 1-12 |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.2011506118 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1073/pnas.2011506118 Verlag, lizenzpflichtig, Volltext: https://www.pnas.org/content/118/26/e2011506118 
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| Author Notes: | Susann Ludewig, Ulrike Herrmann, Kristin Michaelsen-Preusse, Kristin Metzdorf, Jennifer Just, Charlotte Bold, Ulrike C. Müller, and Martin Korte |
| Summary: | 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. |
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| Item Description: | Im Text ist "2+" hochgestellt Gesehen am 19.08.2021 |
| Physical Description: | Online Resource |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.2011506118 |