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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