Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease

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.