ABNORMAL CALCIUM HOMEOSTASIS IN ASTROCYTES FROM THE TRISOMY-16 MOUSE

The regulation of intracellular Ca2+ was investigated in cultured astr ocytes from the trisomy 16 (Ts16) mouse, an animal model for Down synd rome and Alzheimer's disease (AD). The cytoplasmic ionized Ca2+ concen tration ([Ca2+](cyt)) was determined using digital imaging of fura-2-l oaded cells. The relative Ca2+ content of internal endoplasmic reticul um (ER) stores was estimated from the magnitude of the transient incre ase in [Ca2+](cyt) induced by cyclopiazonic acid (CPA), an inhibitor o f Ca2+ sequestration into ER stores. At rest, the average [Ca2+](cyt) was 140 nhl in euploid (normal) astrocytes, but over twice as high, 32 0 nM, in Ts16 cells. In the absence of extracellular Ca2+, CPA induced a transient increase in [Ca2+](cyt) to over 1200 nM in Ts16 astrocyte s as compared to only 500 nM in euploid cells, indicating an increased amount of Ca2+ in the Ts16 astrocyte ER. In contrast to euploid astro cytes, both resting [Ca2+](cyt) and the amount of Ca2+ in the ER store s varied widely among individual Ts16 astrocytes. These results show t hat Ts16 produces a dysregulation of Ca2+ homeostasis leading to incre ased cytoplasmic and stored Ca2+. Since increases in [Ca2+](cyt) have been implicated in the etiology of neurodegenerative diseases, includi ng 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. (C) 1997 Wile y-Liss, Inc.