A Role for Calcineurin in Alzheimers Disease

Reese, Lindsay C.; Taglialatela, Giulio

doi:10.2174/157015911798376316

Cited by 106 publications

(94 citation statements)

References 100 publications

(127 reference statements)

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“…26) Calcineurin, a Ca 2+ activated protein serine/threonine phosphatase, is abundant in the central nervous system. 27,28) In addition to NFATs, calcineurin substrates include Bcl-2 associated death protein (BAD), 29) N-methyl-D-aspartate (NMDA) receptor, 30) glycogen synthase kinase-3β (GSK-3β), 31) and tau 32) in neuronal cells. Calcineurin activity is also regulated by an endogenous inhibitor, RCAN1.…”

Section: Discussionmentioning

confidence: 99%

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

Kinjo

Kimura

Mori

et al. 2016

Biological & Pharmaceutical Bulletin

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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...

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Section: Discussionmentioning

confidence: 99%

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

Kinjo

Kimura

Mori

et al. 2016

Biological & Pharmaceutical Bulletin

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“…In AD, plasticity and cognition are affected through the perturbation of Ca 2+ /calmodulin-dependent protein kinase II-α (CaMKII) autophosphorylation [32]. Association of A03B2 oligomers with the PSD implicates dephosphorylation (deactivation) of CREB (cAMP response element-binding protein factor), which in turn affects transcription of genes regulating long-term changes in synaptic strength [33]. …”

Section: Introductionmentioning

confidence: 99%

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

Zolochevska

Bjorklund

Woltjer

et al. 2018

JAD

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Some individuals, here referred to as Non-Demented with Alzheimer’s Neuropathology (NDAN), retain their cognitive function despite the presence of amyloid plaques and tau tangles typical of symptomatic Alzheimer’s disease (AD). In NDAN, unlike AD, toxic amyloid-β oligomers do not localize to the postsynaptic densities (PSDs). Synaptic resistance to amyloid-β in NDAN may thus enable these individuals to remain cognitively intact despite the AD-like pathology. The mechanism(s) responsible for this resistance remains unresolved and understanding such protective biological processes could reveal novel targets for the development of effective treatments for AD. The present study uses a proteomic approach to compare the hippocampal postsynaptic densities of NDAN, AD, and healthy age-matched persons to identify protein signatures characteristic for these groups. Subcellular fractionation followed by 2D gel electrophoresis and mass spectrometry were used to analyze the PSDs. We describe fifteen proteins which comprise the unique proteomic signature of NDAN PSDs, thus setting them apart from control subjects and AD patients.

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“…GSK3β activity was implicated in Tau phosphorylation, APP processing, Aβ production, and neurodegeneration [48] . In addition, AβO-induced GSK3β over-activity could lead to glutamate receptor internalization, spine retraction, LTP blockage, and LTD facilitation [4,49] . The blockade of either GSK3β expression or activity decreased Aβ production and plaque accumulation [50] , improved performance in memory tests, preserved the dendritic structure, and reduced the Tau-dependent pathology in AD transgenic models [51,52] .…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage

et al. 2015

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Aim:The proteolytic cleavage of Tau is involved in Aβ-induced neuronal dysfunction and cell death. In this study, we investigated whether atorvastatin could prevent Tau cleavage and hence prevent Aβ 1-42 oligomer (AβO)-induced neurotoxicity in cultured cortical neurons. Methods: Cultured rat hippocampal neurons were incubated in the presence of AβOs (1.25 µmol/L) with or without atorvastatin pretreatment. ATP content and LDH in the culture medium were measured to assess the neuronal viability. Caspase-3/7 and calpain protease activities were detected. The levels of phospho-Akt, phospho-Erk1/2, phospho-GSK3β, p35 and Tau proteins were measured using Western blotting. Results: Treatment of the neurons with AβO significantly decreased the neuronal viability, induced rapid activation of calpain and caspase-3/7 proteases, accompanied by Tau degradation and relatively stable fragments generated in the neurons. AβO also suppressed Akt and Erk1/2 kinase activity, while increased GSK3β and Cdk5 activity in the neurons. Pretreatment with atorvastatin (0.5, 1, 2.5 µmol/L) dose-dependently inhibited AβO-induced activation of calpain and caspase-3/7 proteases, and effectively diminished the generation of Tau fragments, attenuated synaptic damage and increased neuronal survival. Atorvastatin pretreatment also prevented AβO-induced decreases in Akt and Erk1/2 kinase activity and the increases in GSK3β and Cdk5 kinase activity. Conclusion: Atorvastatin prevents AβO-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting calpain-and caspasemediated Tau cleavage.

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A Role for Calcineurin in Alzheimers Disease

Cited by 106 publications

References 100 publications

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

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

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage

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