title: Increased intraneuronal resting [Ca2+] in adult Alzheimer's disease mice.
abstract: Neurodegeneration in Alzheimer's disease (AD) has been linked to intracellular accumulation of misfolded proteins and dysregulation of intracellular Ca2+. In the current work, we determined the contribution of specific Ca2+ pathways to an alteration in Ca2+ homeostasis in primary cortical neurons from an adult triple transgenic (3xTg-AD) mouse model of AD that exhibits intraneuronal accumulation of beta-amyloid proteins. Resting free Ca2+ concentration ([Ca2+](i)), as measured with Ca2+-selective microelectrodes, was greatly elevated in neurons from 3xTg-AD and APP(SWE) mouse strains when compared with their respective non-transgenic neurons, while there was no alteration in the resting membrane potential. In the absence of the extracellular Ca2+, the [Ca2+](i) returned to near normal levels in 3xTg-AD neurons, demonstrating that extracellular Ca2+contributed to elevated [Ca2+](i). Application of nifedipine, or a non-L-type channel blocker, SKF-96365, partially reduced [Ca2+](i). Blocking the ryanodine receptors, with ryanodine or FLA-365 had no effect, suggesting that these channels do not contribute to the elevated [Ca2+](i). Conversely, inhibition of inositol trisphosphate receptors with xestospongin C produced a partial reduction in [Ca2+](i). These results demonstrate that an elevation in resting [Ca2+](i), contributed by aberrant Ca2+entry and release pathways, should be considered a major component of the abnormal Ca2+ homeostasis associated with AD.
authors.affiliation: Department of Anesthesia, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: José R
authors.initials: JR
authors.lastname: Lopez
authors.forename: Alvin
authors.initials: A
authors.lastname: Lyckman
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oddo
authors.forename: Frank M
authors.initials: FM
authors.lastname: Laferla
authors.forename: Henry W
authors.initials: HW
authors.lastname: Querfurth
authors.forename: Alexander
authors.initials: A
authors.lastname: Shtifman
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019579:Neocortex / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D012433:Ryanodine / Q000494:pharmacology; D016875:tau Proteins / Q000235:genetics
chemical_list: D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins; D012433:Ryanodine; D002118:Calcium