Role of Presenilins in Neuronal Calcium Homeostasis

Alzheimer9s disease (AD) is a progressive and irreversible neurodegenerative disorder. Familial AD (FAD) mutations in presenilins have been linked to calcium (Ca 2+ ) signaling abnormalities. To explain these results, we previously proposed that presenilins function as endoplasmic reticulum (ER) passive Ca 2+ leak channels. To directly investigate the role of presenilins in neuronal ER Ca 2+ homeostasis, we here performed a series of Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ leak function of presenilins may play an important role in AD pathogenesis.