G. Ermak et al., Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease, J BIOL CHEM, 276(42), 2001, pp. 38787-38794
The DSCR1 (Adapt78) gene was independently discovered as a resident of the
"Down syndrome candidate region" and as an "adaptive response" shock or str
ess gene that is transiently induced during oxidative stress. Recently the
DSCR1 (Adapt78) gene product was discovered to be an inhibitor of the serin
e/threonine phosphatase, calcineurin, and its signaling pathways. We hypoth
esized that DSCR1 (Adapt78) might also be involved in the development of Al
zheimer's disease. To address this question we first studied DSCR1 (Adapt78
) in multiple human tissues and found significant expression in brain, spin
al cord, kidney, liver, mammary gland, skeletal muscle, and heart. Within t
he brain DSCR1 (Adapt78) is predominantly expressed in neurons within the c
erebral cortex, hippocampus, substantia nigra, thalamus, and medulla oblong
ata. When we compared DSCR1 (Adapt78) mRNA expression in post-mortem brain
samples from Alzheimer's disease patients and individuals who had died with
no Alzheimer's diagnosis, we found that DSCR1 (Adapt78) mRNA levels were a
bout twice as high in age-matched Alzheimer's patients as in controls. DSCR
1 (Adapt78) mRNA levels were actually three times higher in patients with e
xtensive neurofibrillary tangles (a hallmark of Alzheimer's disease) than i
n controls. In comparison, postmortem brain samples from Down syndrome pati
ents (who suffer Alzheimer's symptoms) also exhibited DSCR1 (Adapt78) mRNA
levels two to three times higher than controls. Using a cell culture model
we discovered that the amyloid beta (1-42) peptide, which is a major compon
ent of senile plaques in Alzheimer's, can directly induce increased express
ion of DSCR1 (Adapt78). Our findings associate DSCR1 (Adapt78) with such ma
jor hallmarks of Alzheimer's disease as amyloid protein, senile plaques, an
d neurofibrillary tangles.