Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome

Liu, Fei; Liang, Zhihou; Węgiel, Jerzy; Hwang, Yu-Wen; Iqbal, Khalid; Grundke‐Iqbal, Inge; Ramakrishna, Narayan; Chen, Gong

doi:10.1096/fj.07-104539

Cited by 225 publications

(262 citation statements)

References 61 publications

(63 reference statements)

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“…In fact, high levels of DYRK1A have been found in the cerebral cortex of patients with AD and DS (Ferrer et al, 2005). Moreover, aberrant phosphorylation of tau has also been reported in TS and Ts1Cje mice (Liu et al, 2008;Shukkur et al, 2006) and in CTb cells derived from the cerebral cortex of Ts16 animals (Cárdenas et al, 2012).…”

Section: Implication Of Dyrk1a In Tau Hyperphosphorylationmentioning

confidence: 99%

“…TS mice replicate many DS-like abnormalities, including alterations in behavior, learning and memory, brain morphology and hypocellularity, neurogenesis, neuronal connectivity and electrophysiological and neurochemical processes (Rueda et al, 2012;Bartesaghi et al, 2011). Similar to DS individuals, the TS mouse also shows age-dependent cognitive decline and degeneration starting at the age of 6 months, including cholinergic and noradrenergic neuron degeneration, increases in the levels of APP protein and Aβ peptides and tau hyperphosphorylation (Millan Sanchez et al, 2012;Rueda et al, 2010;Netzer et al, 2010;Liu et al, 2008;Seo et al, 2005). However, these animals do not show amyloid plaques or neurofibrillary tangles.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…DYRK1A phosphorylates tau at the Thr212 residue in vitro (Liu et al, 2008;Woods et al, 2001), in the brains of transgenic mice that overexpress the human DYRK1A protein (TgDYRK1A mice) (Ryoo et al, 2007) and in the brains of patients with AD (Morishima-Kawashima et al, 1995). DYRK1A also phosphorylates Ser202 (Ryoo et al, 2007), and the levels of phosphorylated tau at…”

Section: Implication Of Dyrk1a In Tau Hyperphosphorylationmentioning

confidence: 99%

“…The first evidence of the role of DYRK1A in tauopathies came from several in vitro studies demonstrating that it phosphorylates at least 12 of tau residues including the threonine 212 (Thr212) (Park and Chung, 2013;Liu et al, 2008;Woods et al, 2001). In addition, there is evidence of its in vivo role in tau hyperphosphorylation in transgenic mice that overexpress Dyrk1A alone (TgDyrk1A) (Ryoo et al, 2007), in mice with a partial trisomy of a group of genes including Dyrk1A (such as the Ts65Dn mouse, see below) (Liu et al, 2008), in the transchromosomic mouse model Tc1 (Sheppard et al, 2012) and in the temporal cortex of DS individuals (Qian et al, 2013;Liu et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, there is evidence of its in vivo role in tau hyperphosphorylation in transgenic mice that overexpress Dyrk1A alone (TgDyrk1A) (Ryoo et al, 2007), in mice with a partial trisomy of a group of genes including Dyrk1A (such as the Ts65Dn mouse, see below) (Liu et al, 2008), in the transchromosomic mouse model Tc1 (Sheppard et al, 2012) and in the temporal cortex of DS individuals (Qian et al, 2013;Liu et al, 2008). These results indicate that DYRK1A overexpression contributes to the appearance of neurofibrillary tangles and their subsequent neurotoxicity (Park and Chung, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

García-Cerro

Rueda

Vidal

et al. 2017

Neurobiology of Disease

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The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dualspecificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Aβ, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aβ load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.

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Section: Implication Of Dyrk1a In Tau Hyperphosphorylationmentioning

confidence: 99%

Section: Accepted Manuscriptmentioning

confidence: 99%

Section: Implication Of Dyrk1a In Tau Hyperphosphorylationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

García-Cerro

Rueda

Vidal

et al. 2017

Neurobiology of Disease

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C‐terminal truncation of GSK‐3β enhances its dephosphorylation by PP2A

Jin

Wen

et al. 2017

FEBS Letters

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Glycogen synthase kinase-3β (GSK-3β) is the major tau kinase. Its phosphorylation at Ser9 suppresses the activity. In Alzheimer's disease (AD) brain, GSK-3β is truncated at the C terminus by overactivated calpain I, leading to an increase in its activity. However, the effect of truncation on its phosphorylation is unknown. We found here that in AD brain and in cultured cells, C-terminally truncated GSK-3β is less phosphorylated at Ser9 than the full-length enzyme. The truncation promotes GSK-3β nuclear translocation and enhances its interaction with protein phosphatase 2A (PP2A), leading to dephosphorylation. Thus, the truncation of GSK-3β may enhance its activity through Ser9 dephosphorylation by PP2A. Our findings shed new light on the role of calpain-GSK-3β-PP2A in tau pathogenesis of AD.

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Impact of increased APP gene dose in Down syndrome and the Dp16 mouse model

Sawa

Overk

Becker

et al. 2021

Alzheimer's & Dementia

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Introduction:People with Down syndrome (DS) are predisposed to Alzheimer's disease (AD). The amyloid hypothesis informs studies of AD. In AD-DS, but not sporadic AD, increased APP copy number is necessary, defining the APP gene dose hypothesis.Which amyloid precursor protein (APP) products contribute needs to be determined. Methods: Brain levels of full-length protein (fl-hAPP), C-terminal fragments (hCTFs), and amyloid beta (Aβ) peptides were measured in DS, AD-DS, non-demented controls (ND), and sporadic AD cases. The APP gene-dose hypothesis was evaluated in the Dp16 model. Results: DS and AD-DS differed from ND and AD for all APP products. In AD-DS, Aβ42 and Aβ40 levels exceeded AD. APP products were increased in the Dp16 model; increased APP gene dose was necessary for loss of vulnerable neurons, tau pathology, and activation of astrocytes and microglia.

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Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome

Cited by 225 publications

References 61 publications

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

C‐terminal truncation of GSK‐3β enhances its dephosphorylation by PP2A

Impact of increased APP gene dose in Down syndrome and the Dp16 mouse model

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