Abnormal calcium homeostasis in astrocytes from the trisomy 16 mouse.
The regulation of intracellular Ca2+ was investigated in cultured astrocytes from the trisomy 16 (Ts16) mouse, an animal model for Down syndrome and Alzheimer's disease (AD). The cytoplasmic ionized Ca2+ concentration ([Ca2+]cyt) was determined using digital imaging of fura-2-loaded cells. The relative Ca2+ content of internal endoplasmic reticulum (ER) stores was estimated from the magnitude of the transient increase in [Ca2+]cyt induced by cyclopiazonic acid (CPA), an inhibitor of Ca2+ sequestration into ER stores. At rest, the average [Ca2+]cyt was 140 nM in euploid (normal) astrocytes, but over twice as high, 320 nM, in Ts16 cells. In the absence of extracellular Ca2+, CPA induced a transient increase in [Ca2+]cyt to over 1200 nM in Ts16 astrocytes as compared to only 500 nM in euploid cells, indicating an increased amount of Ca2+ in the Ts16 astrocyte ER. In contrast to euploid astrocytes, both resting [Ca2+]cyt and the amount of Ca2+ in the ER stores varied widely among individual Ts16 astrocytes. These results show that Ts16 produces a dysregulation of Ca2+ homeostasis leading to increased cytoplasmic and stored Ca2+. Since increases in [Ca2+]cyt have been implicated in the etiology of neurodegenerative diseases, including AD, this finding of abnormal Ca2+ homeostasis in a genetic model of human neurological disorders suggests that Ca2+ dysregulation may be a common feature underlying neurodegenerative processes.
Bambrick
L L
LL
Department of Physiology, University of Maryland, School of Medicine, Baltimore, USA.
Golovina
V A
VA
Blaustein
M P
MP
Yarowsky
P J
PJ
Krueger
B K
BK
D000544:Alzheimer Disease; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D004314:Down Syndrome; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016257:Fura-2; D006706:Homeostasis; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008818:Mice, Neurologic Mutants; D008856:Microscopy, Fluorescence
D004791:Enzyme Inhibitors; D007211:Indoles; D000252:Calcium-Transporting ATPases; D002118:Calcium; D016257:Fura-2; C000543:cyclopiazonic acid