title: 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.
authors.affiliation: School of Pharmaceutical Sciences, Nagasaki University.
authors.forename: Masashi
authors.initials: M
authors.lastname: Asai
authors.forename: Aimi
authors.initials: A
authors.lastname: Kinjo
authors.forename: Shoko
authors.initials: S
authors.lastname: Kimura
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Mori
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawakubo
authors.forename: Keiro
authors.initials: K
authors.lastname: Shirotani
authors.forename: Sosuke
authors.initials: S
authors.lastname: Yagishita
authors.forename: Kei
authors.initials: K
authors.lastname: Maruyama
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D061207:Calcium Ionophores / Q000494:pharmacology; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004314:Down Syndrome / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D015759:Ionomycin / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016875:tau Proteins / Q000235:genetics
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D065095:Calcineurin Inhibitors; D061207:Calcium Ionophores; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; C108612:RCAN1 protein, human; D012333:RNA, Messenger; D016875:tau Proteins; D015759:Ionomycin; D016572:Cyclosporine; D008156:Luciferases; D019703:Calcineurin; D015260:Neprilysin; D013755:Tetradecanoylphorbol Acetate