RCAN1 overexpression promotes age-dependent mitochondrial dysregulation related to neurodegeneration in Alzheimer’s disease

Wong, Helen; Levenga, Josien; Cain, Peter; Rothermel, Beverly A.; Klann, Eric; Hoeffer, Charles A.

doi:10.1007/s00401-015-1499-8

Cited by 61 publications

(90 citation statements)

References 64 publications

(119 reference statements)

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“…Similar to this, PC12 cells stably overexpressing RCAN1 have an increased susceptibility to oxidative stress and produce more mitochondrial reactive oxygen species . Furthermore, brain‐specific overexpression of human RCAN1.1 in mice reproduces key AD features including early age‐dependent memory and synaptic plasticity deficits, tau pathology, and mitochondrial dysfunction and oxidative stress . Alterations in RCAN1.1 and RCAN1.4 levels have also been shown to affect well known Caspase‐mediated neuronal apoptosis pathways.…”

Section: Neurological Functionmentioning

confidence: 61%

“…16 Furthermore, brain-specific overexpression of human RCAN1.1 in mice reproduces key AD features including early age-dependent memory and synaptic plasticity deficits, tau pathology, and mitochondrial dysfunction and oxidative stress. 42 Alterations in RCAN1.1 and RCAN1.4 levels have also been shown to affect well known Caspase-mediated neuronal apoptosis pathways. Overexpressing RCAN1.1 in rat neurons resulted in elevated apoptosis via Caspase-9 and Caspase-3 mediated pathways.…”

Section: Neurological Functionmentioning

confidence: 99%

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The neuronal and endocrine roles of RCAN1 in health and disease

Peiris

Keating

2017

Clin Exp Pharma Physio

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The regulator of calcineurin 1 (RCAN1) was first discovered as a gene located on human chromosome 21, expressed in neurons and overexpressed in the brains of Down syndrome individuals. Increased expression of RCAN1 has been linked with not only Down syndrome-associated pathology but also an associated neurological disorder, Alzheimer's Disease, in which neuronal RCAN1 expression is also increased. RCAN1 has additionally been demonstrated to affect other cell types including endocrine cells, with links to the pathogenesis of β-cell dysfunction in type 2 diabetes. The primary functions of RCAN1 relate to the inhibition of the phosphatase calcineurin, and to the regulation of mitochondrial function. Various forms of cellular stress such as reactive oxygen species and hyperglycaemia cause transient increases in RCAN1 expression. The short term (hours to days) induction of RCAN1 expression is generally thought to have a protective effect by regulating the expression of pro-survival genes in multiple cell types, many of which are mediated via the calcineurin/NFAT transcriptional pathway. However, strong evidence also supports the notion that chronic (weeks-years) overexpression of RCAN1 has a detrimental effect on cells and that this may drive pathophysiological changes in neurons and endocrine cells linked to Down syndrome, Alzheimer's Disease and type 2 diabetes. Here we review the evidence related to these roles of RCAN1 in neurons and endocrine cells and their relationship to these human health disorders.

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Section: Neurological Functionmentioning

confidence: 61%

Section: Neurological Functionmentioning

confidence: 99%

The neuronal and endocrine roles of RCAN1 in health and disease

Peiris

Keating

2017

Clin Exp Pharma Physio

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“…Akt1 KO 46 , Akt2 KO 13 and Akt3 KO 11 male mice were generated in the C57/BL6 background. To generate mice that have conditional Akt1 or Akt2 removal in excitatory neurons in the forebrain we bred Akt1 loxP/loxP 47 or Akt2 loxP/loxP 48 with Camk2α - Cre (T-29-1) 49 or NSE39-Cre (Jax Labs) mice, all in the C57/BL6 background. Age-matched wild-type (WT) male littermates were used as controls for this study.…”

Section: Methodsmentioning

confidence: 99%

AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity

Levenga

Wong

Milstead

et al. 2017

Preprint

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13AKT is a kinase that regulates numerous cellular processes in the brain and mutations in AKT 14 are known to affect brain function. AKT is indirectly implicated in synaptic plasticity, but its direct 15 role has not been studied. Moreover, three highly related AKT isoforms are expressed in the 16 brain, but their individual roles are poorly understood. We find that each AKT isoform has a 17 unique expression pattern in the hippocampus, with AKT1 and AKT3 primarily in neurons but 18 displaying local differences, while AKT2 is in astrocytes. We also find isoform-specific roles for 19 AKT in multiple paradigms of hippocampal synaptic plasticity. AKT1, but not AKT2 or AKT3, is 20 required for L-LTP through regulating activity-induced protein synthesis. Interestingly, AKT 21 activity inhibits mGluR-LTD, with overlapping functions for AKT1 and AKT3. In summary, our 22

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“…The genes encoding DYRK1A and regulator of calcineurin 1 [RCAN1; also known as calcipressin-1 or DS critical region protein 1 (DSCR1)] are strongly associated with DS phenotypes 19) and have been suggested to have a relationship with the AD pathogenesis. 20,21) The mRNA levels of APP, DYRK1A and RCAN1 were significantly higher in the DS fibroblasts than in fibroblasts from healthy controls (control fibroblasts), except that in DS fibroblast Detroit 539 the expression of DYRK1A was significantly lower than that in control fibroblast TIG-119. Interestingly, the DS fibroblasts showed lower levels of MME, which encodes NEP, compared with the control fibroblasts.…”

Section: Resultsmentioning

confidence: 97%

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

Kawakubo

Mori

Shirotani

et al. 2017

Biological & Pharmaceutical Bulletin

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Amyloid-β peptide (Aβ) accumulation is a triggering event leading to the Alzheimer's disease (AD) pathological cascade. Almost all familial AD-linked gene mutations increase Aβ production and accelerate the onset of AD. The Swedish mutation of amyloid precursor protein (APP) affects β-secretase activity and increases Aβ production up to ca. 6-fold in cultured cells; the onset age is around 50. Down syndrome (DS) patients with chromosome 21 trisomy present AD-like pathologies at earlier ages (40s) compared with sporadic AD patients, because APP gene expression is 1.5-fold higher than that in healthy people, thus causing a 1.5-fold increase in Aβ production. However, when comparing the causal relationship of Aβ accumulation with the onset age between the above two populations, early DS pathogenesis does not appear to be accounted for by the increased Aβ production alone. In this study, we found that neprilysin, a major Aβ-degrading enzyme, was downregulated in DS patient-derived fibroblasts, compared with healthy people-derived fibroblasts. Treatment with harmine, an inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), which is located in the DS critical region of chromosome 21, and gene knockdown of DYRK1A, upregulated neprilysin in fibroblasts. These results suggest that a decrease in the Aβ catabolic rate may be, at least in part, one of the causes for accelerated AD-like pathogenesis in DS patients if a similar event occurs in the brains, and that neprilysin activity may be regulated directly or indirectly by DYRK1A-mediated phosphorylation. DYRK1A inhibition may be a promising disease-modifying therapy for AD via neprilysin upregulation.Key words Alzheimer's disease; chromosome 21; down syndrome; dual-specificity tyrosine phosphorylationregulated kinase 1A; neprilysin Alzheimer's disease (AD) brains are pathologically characterized by numerous senile plaques and neurofibrillary tangles, which consist of aggregation amyloid-β peptide (Aβ) and hyperphosphorylated tau, respectively, and prominent neuronal cell death. Aβ is generated from amyloid precursor protein (APP) by β-and γ-secretase-mediated sequential cleavages, followed by Aβ degradation by neprilysin (NEP). Aβ in healthy brains is maintained at a constant level by an equilibrium between the production and degradation rates. 1)An imbalance arising by a subtle change in either rate leads to Aβ accumulation.The Swedish double mutation (K670N/M671L) in APP, one of the most well-known mutations in familial AD, leads to a dramatic increase in total Aβ production.2,3) The average onset age of Swedish familial AD is around 55 years.4) On the other hand, Down syndrome (DS) is one of the most frequently occurring chromosomal abnormalities. 5,6) Approximately 95% of DS is caused by standard trisomy 21, which is an extra copy of chromosome 21. The remaining causes, chromosomal translocation and mosaicism, account for 1-5 and 1-2% of DS cases, respectively. DS patients have unique physical characteristics and suffer from various comp...

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RCAN1 overexpression promotes age-dependent mitochondrial dysregulation related to neurodegeneration in Alzheimer’s disease

Cited by 61 publications

References 64 publications

The neuronal and endocrine roles of RCAN1 in health and disease

The neuronal and endocrine roles of RCAN1 in health and disease

AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity

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

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