期刊
JOURNAL OF NEUROSCIENCE
卷 30, 期 25, 页码 8566-8580出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1554-10.2010
关键词
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资金
- Alzheimer's Association
- Alzheimer's Disease Drug Discovery Foundation
- McKnight Brain Disorders Award
- National Institutes of Health [R01AG030746]
- Flemish government
- Katholieke Universiteit Leuven
- Fund for Scientific Research (Flanders, Belgium)
- Federal Office for Scientific Affairs [IUAP P6/43]
- European Union [F2-2007-200611]
Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder. Familial AD (FAD) mutations in presenilins have been linked to calcium (Ca2+) signaling abnormalities. To explain these results, we previously proposed that presenilins function as endoplasmic reticulum (ER) passive Ca2+ leak channels. To directly investigate the role of presenilins in neuronal ER Ca2+ homeostasis, we here performed a series of Ca2+ imaging experiments with primary neuronal cultures from conditional presenilin double-knock-out mice (PS1(dTAG/dTAG), PS2(-/-)) and from triple-transgenic AD mice (KI-PS1(M146V), Thy1-APP(KM670/671NL), Thy1-tau(P301L)). Obtained results provided additional support to the hypothesis that presenilins function as ER Ca2+ leak channels in neurons. Interestingly, we discovered that presenilins play a major role in ER Ca2+ leak function in hippocampal but not in striatal neurons. We further discovered that, in hippocampal neurons, loss of presenilin-mediated ER Ca2+ leak function was compensated by an increase in expression and function of ryanodine receptors (RyanRs). Long-term feeding of the RyanR inhibitor dantrolene to amyloid precursor protein-presenilin-1 mice (Thy1-APP(KM670/671NL), Thy1-PS1(L166P)) resulted in an increased amyloid load, loss of synaptic markers, and neuronal atrophy in hippocampal and cortical regions. These results indicate that disruption of ER Ca2+ leak function of presenilins may play an important role in AD pathogenesis.
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