Perturbed Calcineurin-NFAT Signaling Is Associated with the Development of Alzheimer’s Disease

Abstract

Down syndrome (DS), the most common genetic disorder, is caused by trisomy 21. DS is accompanied by heart defects, hearing and vision problems, obesity, leukemia, and other conditions, including Alzheimer's disease (AD). In comparison, most cancers are rare in people with DS. Overexpression of dual specificity tyrosine-phosphorylation-regulated kinase 1A and a regulator of calcineurin 1 located on chromosome 21 leads to excessive suppression of the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, resulting in reduced expression of a critical angiogenic factor. However, it is unclear whether the calcineurin-NFAT signaling pathway is involved in AD pathology in DS patients. Here, we investigated the association between the calcineurin-NFAT signaling pathway and AD using neuronal cells. Short-term pharmacological stimulation decreased gene expression of tau and neprilysin, and long-term inhibition of the signaling pathway decreased that of amyloid precursor protein. Moreover, a calcineurin inhibitor, cyclosporine A, also decreased neprilysin activity, leading to increases in amyloid-β peptide levels. Taken together, our results suggest that a dysregulation in calcineurin-NFAT signaling may contribute to the early onset of AD in people with DS.Key words Alzheimer's disease; Down syndrome; calcineurin; neprilysin; nuclear factor of activated T cell (NFAT); tau Down syndrome (DS) is the most frequent congenital chromosomal disorder, and is primarily caused by an extra copy of chromosome 21. The incidence of DS, approximately one in 600-800 live births, increases with maternal age.1,2) The characteristic physical features of the disease include a flattened face and nose, small head, ears and mouth, wide, short hands with short fingers, dry skin, and decreased or poor muscle tone. Children with DS are at increased risk of complications, including heart defects, hearing and vision problems, obesity, leukemia, and other conditions. 3-5) DS patients in middle age are more susceptible to the development of Alzheimer's disease (AD), 6,7) whereas most cancers are rare in people with DS, in whom overall cancer mortality is below 10% of that in the general population. 8)Vascular endothelial growth factor (VEGF) plays a central role in tumor development.9,10) VEGF and the calcineurinnuclear factor of activated T cells (NFAT) signaling pathway regulates cancer metastasis.9) The Ca 2+ /calmodulin-dependent serine/threonine phosphatase calcineurin dephosphorylates NFAT in the cytoplasm, leading to its nuclear translocation and activation.9,11,12) Dual specificity tyrosine-phosphorylationregulated kinase 1A (DYRK1A) phosphorylates NFAT in the nucleus, leading to its cytoplasmic translocation and inactivation.9,12) Calcineurin is negatively regulated by the DS critical region protein regulator of calcineurin 1 (RCAN1) in the cytoplasm. 9,12) The genes for both DYRK1A and RCAN1 are located on chromosome 21. The calcineurin-NFAT signaling pathway is perturbed by the increased dosage of DYRK1A and RCAN1 in DS pa...

Pretreatment with nimodipine reduces incidence of POCD by decreasing calcineurin mediated hippocampal neuroapoptosis in aged rats

“…Direct activation of the Ca 2+ dependent protease, CaN, appears to represent the target for Ca 2+ action in apoptosis. CaN-mediated enzyme reaction is a feature of some animal models of neurodegenerative disease, for example, Alzheimer’s disease [ 27 ] and cerebral ischemia-reperfusion injury [ 28 ]. Caspase-3 which is mainly involved in the process of apoptosis is the main executor of apoptosis.…”

NFAT1-Mediated Regulation of NDEL1 Promotes Growth and Invasion of Glioma Stem-like Cells

“…Genetic variation and altered enzymatic activities of NDEL1 have been identified in schizophrenia (44). Abnormal NFAT1 activation has been associated with cognitive impairment and psychiatric illness (50). Because the exact role of NFAT1 and NDEL1 in mental illness is still unclear, caution should be taken when targeting NFAT1-NDEL1 signaling.…”

Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts

“…28) However, long-term inhibition of the calcineurin-NFAT signaling pathway by the calcineurin inhibitor, cyclosporine A, showed no effects on the expression level of MME mRNA in human neuroblastoma SH-SY5Y cells. 17) Therefore, the transcription factor, NFAT, may not be directly responsible for the regulation of MME gene expression. Apart from NFAT, genes encoding transcription factors and regulators (e.g., BACH1, GABPA, ERG, ETS2, RUNX1 and SIM2) are located on chromosome 21, and some of them have been reported to be upregulated in DS patients.…”

“…RNA isolation, cDNA synthesis and real-time PCR were performed as previously reported. 17) All data were normalized to the endogenous reference gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. The following primers were used for quantitative RT-PCR amplifications: APP: forward: 5′-GGG TTC AAA CAA AGG TGC AAT C-3′, reverse: 5′-TGC TGC ATC TTG GAC AGG TG-3′; DYRK1A: forward: 5′-TGA TTG CAC CAA CAG GTC CAG-3′, reverse: 5′-AGG CAG CGT AAT CTC AAC ACG A-3′; RCAN1: forward: 5′-AGC ACT TGC TTG CGG AAC TC-3′, reverse: 5′-AGT TAC ACG TTG CAC GGT TGG-3′; MME: forward: 5′-GGG AGC TGA TGA AAC TCA CAA ATG-3′, reverse: 5′-TCT CTG GAC AGC TTG CAC CTA C-3′; GAPDH: forward: 5′-GCA CCG TCA AGG CTG AGA AC-3′, reverse: 5′-TGG TGA AGA CGC CAG TGG A-3′.…”