Enhanced caffeine-induced Ca2+ release in the 3xTg-AD mouse model of Alzheimer's disease

Ian F. Smith, Brian Hitt, Kim N. Green, Salvatore Oddo, Frank M. LaFerla

Research output: Contribution to journalArticle

121 Scopus citations

Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia among the elderly and is a complex disorder that involves altered proteolysis, oxidative stress and disruption of ion homeostasis. Animal models have proven useful in studying the impact of mutant AD-related genes on other cellular signaling pathways, such as Ca2+ signaling. Along these lines, disturbances of intracellular Ca2+ ([Ca2+]i) homeostasis are an early event in the pathogenesis of AD. Here, we have employed microfluorimetric measurements of [Ca2+]i to investigate disturbances in Ca2+ homeostasis in primary cortical neurons from a triple transgenic mouse model of Alzheimer's disease (3xTg-AD). Application of caffeine to mutant presenilin-1 knock-in neurons (PS1KI) and 3xTg-AD neurons evoked a peak rise of [Ca2+]i that was significantly greater than those observed in non-transgenic neurons, although all groups had similar decay rates of their Ca2+ transient. This finding suggests that Ca 2+ stores are greater in both PS1KI and 3xTg-AD neurons as calculated by the integral of the caffeine-induced Ca2+ transient signal. Western blot analysis failed to identify changes in the levels of several Ca2+ binding proteins (SERCA-2B, calbindin, calsenilin and calreticulin) implicated in the pathogenesis of AD. However, ryanodine receptor expression in both PS1KI and 3xTg-AD cortex was significantly increased. Our results suggest that the enhanced Ca2+ response to caffeine observed in both PS1KI and 3xTg-AD neurons may not be attributable to an alteration of endoplasmic reticulum store size, but to the increased steady-state levels of the ryanodine receptor.

Original languageEnglish (US)
Pages (from-to)1711-1718
Number of pages8
JournalJournal of Neurochemistry
Volume94
Issue number6
DOIs
StatePublished - Sep 1 2005
Externally publishedYes

Keywords

  • Alzheimer's
  • Caffeine
  • Calcium
  • Neuron
  • Presenilin
  • Ryanodine

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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