title: Capacitive calcium entry is directly attenuated by mutant presenilin-1, independent of the expression of the amyloid precursor protein.
abstract: Mutant presenilin-1 (PS1) increases amyloid peptide production, attenuates capacitative calcium entry (CCE), and augments calcium release from the endoplasmatic reticulum (ER). Here we measured the intracellular free Ca(2+) concentration in hippocampal neurons from six different combinations of transgenic and gene-ablated mice to demonstrate that mutant PS1 attenuated CCE directly, independent of the expression of the amyloid precursor protein (APP). On the other hand, increased Ca(2+) release from the ER in mutant PS1 neurons, as induced by thapsigargin, was clearly dependent on the presence of APP and its processing by PS1, i.e. on the generation of the amyloid peptides and the APP C99 fragments. This observation was corroborated by the thapsigargin-induced increase in cytosolic [Ca(2+)](i) in PS1 deficient neurons, which accumulate C99 fragments due to deficient gamma-secretase activity. Moreover, co-expression of mutant APP[V717I] in PS1-deficient neurons further increased the apparent size of the ER calcium stores in parallel with increasing levels of the APP processing products. We conclude that mutant PS1 deregulates neuronal calcium homeostasis by two different actions: (i) direct attenuation of CCE at the cell-surface independent of APP; and (ii) indirect increase of ER-calcium stores via processing of APP and generation of amyloid peptides and C99 fragments.
authors.affiliation: Department of Neuropathology, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Herms
authors.forename: Ilka
authors.initials: I
authors.lastname: Schneider
authors.forename: Ilse
authors.initials: I
authors.lastname: Dewachter
authors.forename: Nathalie
authors.initials: N
authors.lastname: Caluwaerts
authors.forename: Hans
authors.initials: H
authors.lastname: Kretzschmar
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D053764:Presenilin-1; D013997:Time Factors
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D010455:Peptides; D053764:Presenilin-1; D002118:Calcium