TY - JOUR
T1 - Role of presenilins in neuronal calcium homeostasis
AU - Zhang, Hua
AU - Sun, Suya
AU - Herreman, An
AU - De Strooper, Bart
AU - Bezprozvanny, Ilya
PY - 2010/6/23
Y1 - 2010/6/23
N2 - 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-PS1M146V, Thy1-APPKM670/671NL, Thy1-tauP 301L). 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 Ca 2+ 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-APPKM670/671NL, Thy1-PS1L166P) 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.
AB - 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-PS1M146V, Thy1-APPKM670/671NL, Thy1-tauP 301L). 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 Ca 2+ 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-APPKM670/671NL, Thy1-PS1L166P) 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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U2 - 10.1523/JNEUROSCI.1554-10.2010
DO - 10.1523/JNEUROSCI.1554-10.2010
M3 - Article
C2 - 20573903
AN - SCOPUS:77954123379
SN - 0270-6474
VL - 30
SP - 8566
EP - 8580
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 25
ER -