Increased intraneuronal resting [Ca2+] in adult Alzheimer's disease mice

José R. Lopez, Alvin Lyckman, Salvatore Oddo, Frank M. LaFerla, Henry W. Querfurth, Alexander Shtifman

Research output: Contribution to journalArticle

104 Scopus citations

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 Ca 2+ homeostasis in primary cortical neurons from an adult triple transgenic (3xTg-AD) mouse model of AD that exhibits intraneuronal accumulation of β-amyloid proteins. Resting free Ca2+ concentration ([Ca 2+]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.

Original languageEnglish (US)
Pages (from-to)262-271
Number of pages10
JournalJournal of Neurochemistry
Volume105
Issue number1
DOIs
StatePublished - Apr 2008
Externally publishedYes

Keywords

  • β-amyloid
  • Alzheimer's disease
  • Ca entry
  • Inositol trisphosphate receptors
  • L-type channels
  • Ryanodine receptors

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Lopez, J. R., Lyckman, A., Oddo, S., LaFerla, F. M., Querfurth, H. W., & Shtifman, A. (2008). Increased intraneuronal resting [Ca2+] in adult Alzheimer's disease mice. Journal of Neurochemistry, 105(1), 262-271. https://doi.org/10.1111/j.1471-4159.2007.05135.x