Role of presenilins in neuronal calcium homeostasis.
Alzheimer's 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.
Zhang
Hua
H
Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
Sun
Suya
S
Herreman
An
A
De Strooper
Bart
B
Bezprozvanny
Ilya
I
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001284:Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003620:Dantrolene / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D053763:Presenilins / Q000235:genetics / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
D016229:Amyloid beta-Peptides; D053763:Presenilins; D019837:Ryanodine Receptor Calcium Release Channel; D003620:Dantrolene; D002118:Calcium