Abstract
Down Syndrome (DS) patients develop characteristic Alzheimer's Disease (AD) neuropathology after their middle age. Prominent neuronal loss has been observed in the cortical regions of AD brains. However, the underlying mechanism leading to this neuronal loss in both DS and AD remains to be elucidated. Calcium overloading and oxidative stress have been implicated in AD pathogenesis. Two major isoforms of regulator of calcineurin 1 (RCAN1), RCAN1.1 and RCAN1.4, are detected in human brains. In this report we defined the transcriptional regulation of RCAN1.1 and RCAN1.4 by two alternative promoters. Calcium overloading upregulated RCAN1.4 expression by activating RCAN1.4 promoter through calcineurin-NFAT signaling pathway, thus forming a negative feedback loop in isoform 4 regulation. Furthermore, RCAN1.4 overexpression exacerbated calcium overloading-induced neuronal apoptosis, which was mediated by caspase-3 apoptotic pathway. Our results suggest that downregulating RCAN1.4 expression in neurons could be beneficial to AD patients.
Highlights
Down Syndrome (DS) is caused by an extra copy of chromosome 21 and affects approximately one in 800 to 1,000 babies [1,2,3]
To examine whether regulator of calcineurin 1 (RCAN1).4 expression is distinctly regulated by an alternative promoter at transcription level, a 1200-bp fragment from 59UTR of RCAN1 exon 4 was amplified by PCR and sequenced (Fig. 1B)
Our data showed that calcium overload significantly increased the expression of RCAN1.4, the role of RCAN1.4 in neuronal apoptosis remains elusive
Summary
Down Syndrome (DS) is caused by an extra copy of chromosome 21 and affects approximately one in 800 to 1,000 babies [1,2,3]. Calcineurin, known as protein phosphatase 2B (PP2B), is a calcium/calmodulin-dependent serine/threonine phosphatase It consists of a catalytic subunit calcineurin A and a regulatory subunit calcineurin B, forming a heterodimer, which is involved in many physiological processes, such as apoptosis and cardiovascular development. Consistent with this, recent studies showed that induction of RCAN1 expression increases tau phosphorylation in PC12 cells, and tau hyperphosphorylation and neurofibrillary tangle formation in transgenic mice [8,9]. These data suggest that apart from the pro-apoptotic effect of RCAN1 in AD pathogenesis, it may contribute to AD pathogenesis by facilitating tau phosphorylation
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