Direct interaction of soluble human recombinant tau protein with Aβ 1–42 results in tau aggregation and hyperphosphorylation by tau protein kinase II

Rank, Kenneth B.; Pauley, Adele M.; Bhattacharya, Keshab; Wang, Zhigang; Evans, David B.; Fleck, Thomas J.; Johnston, Jennifer; Sharma, Satish Kumar

doi:10.1016/s0014-5793(02)02376-1

Cited by 66 publications

(48 citation statements)

References 37 publications

(48 reference statements)

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“…An association between Aβ and hyperphosphorylated tau has been shown (Ribe et al, 2005;Oddo et al, 2003). Soluble Aβ can induce inactivation of phosphatases (Vogelsberg-Ragaglia et al, 2001) and activation of tau kinases (Hoshi et al, 2003;Otth et al, 2002), and promoting tau phosphorylation (Hoshi et al, 2003;Otth et al, 2002;Zheng et al, 2002) and the direct interaction between tau and Aβ induces tau aggregation and hyperphosphorylation (Rank et al, 2002). In addition, tau seems to be required for the neurotoxic effects of Aβ oligomers (Shipton et al, 2011).…”

Section: Interplay Between Dyrk1a Aβ and Taumentioning

confidence: 99%

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: Interplay Between Dyrk1a Aβ and Taumentioning

confidence: 99%

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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“…Amplified toxic interaction between Aβ and tau (directly [261] or via intermediates [262,263] very likely occurs in the endosome in the context of Aβ generation from APP and oligomer formation [175] and the exosomemediated secretion of membrane proteins [197] and thus may account for the seeding of cellular tau aggregates as well as mediating tau lesion spread [163] especially as association of tau with cellular membranes and membrane elements favors tau oligomerization [171][172][173]. Both secretion and trans-synaptic tau movement have been associated with the presence of tauopathy mutations [183,192], suggesting that either the oligomerization or enhanced proteolytic cleavage of tau associated with these mutations result in the formation of more toxic N-and C-terminal fragments, which then may be secreted, possibly via multiple pathways [193].…”

Section: Predisposing Risk Factors To the Development Of Loadmentioning

confidence: 99%

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

Bhatia

Hall

2013

Translational Neuroscience

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Recent investigations into the etiology and pathogenesis of Alzheimer's disease (AD) in the past few years have expanded to include previously unexplored and/or disconnected aspects of AD and related conditions at both the cellular and systemic levels of organization. These include how AD-associated abnormalities affect the cell cycle and neuronal differentiation state and how they recruit signal transduction, membrane trafficking and protein transcytosis mechanisms to produce a neurotoxic syndrome capable of spreading itself throughout the brain. The recent expansion of AD research into intercellular and new aspects of cellular degenerative mechanisms is causing a systemic re-evaluation of AD pathogenesis, including the roles played by well-studied elements, such as the generation of Aβ and tau protein aggregates. It is also changing our view of neurodegenerative diseases as a whole. Here we propose a conceptual framework to account for some of the emerging aspects of the role of tau in AD pathogenesis.

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“…High levels of intracellular Aβ and the accumulation of the secreted form are believed to be central causative factors for AD (reviewed by Ferreira et al, 2010). Tau was shown to interact with APP both in vitro and in vivo (Barbato et al, 2005) and Aβ aggregates promote in vitro tau aggregation in a dose-dependent manner (Rank et al, 2002), suggesting a direct link between senile plaques and neurofibrillary tangles in AD.…”

Section: Introductionmentioning

confidence: 99%

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

Mota¹,

Ferreira²,

Rego³

2014

Neuropharmacology

170

100

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Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly.Alterations capable of causing brain circuitry dysfunctions in AD may take several years to develop. Oligomeric amyloid-beta peptide (Aβ) plays a complex role in the molecular events that lead to progressive loss of function and eventually to neurodegeneration in this devastating disease. Moreover, N-methyl-D-aspartate (NMDA) receptors (NMDARs) activation has been recently implicated in AD-related synaptic dysfunction. Thus, in this review we focus on glutamatergic neurotransmission impairment and the changes in NMDAR regulation in AD, following the description on the role and location of NMDARs at pre-and post-synaptic sites under physiological conditions. In addition, considering that there is currently no effective ways to cure AD or stop its progression, we further discuss the relevance of NMDARs antagonists to prevent AD symptomatology. This review posits additional information on the role played by Aβ in AD and the importance of targeting the tripartite glutamatergic synapse in early asymptomatic and possible reversible stages of the disease through preventive and/or disease-modifying therapeutic strategies.

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Direct interaction of soluble human recombinant tau protein with Aβ 1–42 results in tau aggregation and hyperphosphorylation by tau protein kinase II

Cited by 66 publications

References 37 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

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

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