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Enhanced caffeine‐induced Ca 2+ release in the 3xTg‐AD mouse model of Alzheimer's disease
Author(s) -
Smith Ian F.,
Hitt Brian,
Green Kim N.,
Oddo Salvatore,
LaFerla Frank M.
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03332.x
Subject(s) - presenilin , genetically modified mouse , ryanodine receptor , pathogenesis , homeostasis , hyperphosphorylation , western blot , serca , microbiology and biotechnology , chemistry , biology , endocrinology , transgene , medicine , alzheimer's disease , neuroscience , biochemistry , intracellular , immunology , disease , phosphorylation , atpase , gene , enzyme
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 Ca 2+ signaling. Along these lines, disturbances of intracellular Ca 2+ ([Ca 2+ ] i ) homeostasis are an early event in the pathogenesis of AD. Here, we have employed microfluorimetric measurements of [Ca 2+ ] i to investigate disturbances in Ca 2+ 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 (PS1 KI ) and 3xTg‐AD neurons evoked a peak rise of [Ca 2+ ] i that was significantly greater than those observed in non‐transgenic neurons, although all groups had similar decay rates of their Ca 2+ transient. This finding suggests that Ca 2+ stores are greater in both PS1 KI and 3xTg‐AD neurons as calculated by the integral of the caffeine‐induced Ca 2+ transient signal. Western blot analysis failed to identify changes in the levels of several Ca 2+ binding proteins (SERCA‐2B, calbindin, calsenilin and calreticulin) implicated in the pathogenesis of AD. However, ryanodine receptor expression in both PS1 KI and 3xTg‐AD cortex was significantly increased. Our results suggest that the enhanced Ca 2+ response to caffeine observed in both PS1 KI 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.