期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2011506118
关键词
Alzheimer's disease; APP; Ca2+ homeostasis; synaptic plasticity
资金
- German Research Foundation (DFG) [FOR1332, MU1457/14-1, MU1457/15-1]
- ElseKroner FreseniusStiftung [2014A229]
The study reveals the essential role of the APP family, particularly the ectodomain APPs alpha, in neuronal Ca2+ handling. Additionally, the loss of APP and APLP2 is shown to impair Ca2+ handling, endoplasmic reticulum Ca2+ store refill, and synaptic plasticity.
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-beta- 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 APPs alpha 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 storeoperated Ca2+ channel-associated proteins Stim1 and Stim2. Longterm AAV-mediated expression of APPs alpha, 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 APPs alpha in Ca2+ homeostasis, thereby highlighting its therapeutic potential.
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