Aβ monomer induces phosphorylation of Tau at Ser‐214 through β2AR‐PKA‐JNK signaling pathway

Wu, Hao; Sang, Wei; Huang, Yonglin; Chen, Lintao; Wang, Yuerong; Wu, Xiaoxue; Zhang, Zhuandan; Pei, Yechun; Wang, Dayong

doi:10.1096/fj.201902230rr

Cited by 17 publications

(8 citation statements)

References 40 publications

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“…Aβ monomer induced phosphorylation of tau at Ser214 through both β2AR-cAMP/PKA-JNK and β2AR-GRK signaling pathways. 536 Intracellular binding of soluble Aβ to soluble nonphosphorylated tau, thus promoting tau phosphorylation and Aβ nucleation. 537 However, phosphorylation of Thr212, Ser214, Ser356, and Ser396 completely blocks Aβ42 binding.…”

Section: Impact Of Phosphorylation and Other Ptm On Tau Aggregationmentioning

confidence: 99%

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

et al. 2021

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Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D) and amyotrophic lateral sclerosis (ALS) research, respectively for over many years.While SOD1 is a globular protein with a well-defined 3D structure, the Aβ, tau and α-synuclein proteins belong to the class of intrinsically disordered proteins (IDPs). IDPs are also known to play a critical role in many cellular functions such as signal transduction, cell growth, binding with DNA and RNA, and transcription, and are implicated in the development of cardiovascular problems and cancers 29 . The IDPs involved in neurodegenerative diseases have a few aggregation-prone regions and overall all IDPs have a low mean hydrophobicity and a high mean net charge 30 .IDPs are structurally flexible and lack stable secondary structures in aqueous solution. When isolated, they behave as polymers in a good solvent and their radii of gyration are well described by the Flory scaling law. 31 The insolubility and high self-assembly propensity of IDPs implicated in degenerative diseases have prevented high-resolution structural determination by solution nuclear magnetic resolution (NMR) and X-ray diffraction experiments. Local information at all aggregation steps can be, however, obtained by chemical shifts, residual coupling constants, and J-couplings from NMR, exchange hydrogen/deuterium (H/D) NMR, Raman spectroscopy; and secondary structure from fast Fourier infrared spectroscopy (FTIR) or circular dichroism (CD). Long-range tertiary contacts can be deduced from paramagnetic relaxation enhancement (PRE) NMR spectroscopy and single molecule Förster resonance energy transfer (sm-FRET), and short-range distance contacts can be extracted by cross linked residues determined by mass spectrometry (MS). Low-resolution 3D information of monomers and oligomers can be obtained by ion-mobility mass-spectrometry data (IM/MS) providing cross-collision sections, dynamic light scattering (DLS), pulse field gradient NMR spectroscopy and fluorescence correlation spectroscopy (FCS) providing hydrodynamics radius, small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS), atomic force microscopy (AFM) and transmission electron microscopy (TEM) providing height features of the aggregates, as reported by some o...

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Section: Impact Of Phosphorylation and Other Ptm On Tau Aggregationmentioning

confidence: 99%

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

et al. 2021

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“…However, GRKs 2, 3, 5 and 6 are ubiquitously expressed throughout the body [23, 24] and have been implicated in cancer progression [26], cardiovascular disease [27, 28], inflammatory processes [29, 30] and several neurological disorders, including addictive behaviours [31–33], pain [34, 35], mood disorders [36, 37], schizophrenia [38–40] and Parkinson's Disease (PD) [41–45]. In AD, GRK2 has been postulated as a potential tau kinase [46, 47] and qualitatively associated with NFTs in AD patient brain samples [48]. Single nucleotide polymorphisms in Grk5 alter its subcellular localisation and subsequent tau phosphorylation [49], possibly through modulation of GSK3β activity in vitro and in vivo [49, 50].…”

Section: Introductionmentioning

confidence: 99%

G protein‐coupled receptor kinases are associated with Alzheimer's disease pathology

Guimarães

Swanson

Kofler

2021

Neuropathology Appl Neurobio

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Aim Alzheimer's disease (AD) is characterised by extracellular deposition of amyloid‐β (Aβ) in amyloid plaques and intracellular aggregation and accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFTs). Although several kinases have been identified to contribute to the pathological phosphorylation of tau, kinase‐targeted therapies for AD have not been successful in clinical trials. Critically, the kinases responsible for numerous identified tau phosphorylation sites remain unknown. G protein‐coupled receptor (GPCR) kinases (GRKs) have recently been implicated in phosphorylation of non‐GPCR substrates, for example, tubulin and α‐synuclein, and in neurological disorders, including schizophrenia and Parkinson's disease. Accordingly, we investigated the involvement of GRKs in the pathophysiology of AD. Methods We performed a comprehensive immunohistochemical and biochemical analysis of the ubiquitously expressed GRKs, namely, GRK2, 3, 5 and 6, in postmortem human brain tissue of control subjects and AD patients. Results GRKs display unique cell‐type‐specific expression patterns in neurons, astrocytes and microglia. Levels of GRKs 2, 5 and 6 are specifically decreased in the CA1 region of the AD hippocampus. Biochemical evidence indicates that the GRKs differentially associate with total, soluble and insoluble pools of tau in the AD brain. Complementary immunohistochemical studies indicate that the GRKs differentially colocalise with total tau, phosphorylated tau and NFTs. Notably, GRKs 3 and 5 also colocalise with amyloid plaques. Conclusion These studies establish a link between GRKs and the pathological phosphorylation and accumulation of tau and amyloid pathology in AD brains and suggest a novel role for these kinases in regulation of the pathological hallmarks of AD.

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“… 39 More importantly, it was established in previous research that Aβ may induce the phosphorylation of Tau. 40 Amyloids have been linked to various neurodegenerative diseases and the aggregation of Aβ into oligomers, fibrils, and plaques represent a key molecular finding strongly implicated in the pathogenesis of AD. 41 Aβ is generated by the continuous cleavage of APP by two enzymes, BACE1 and γ-secretase complex.…”

Section: Discussionmentioning

confidence: 99%

Epigallocatechin-3-Gallate Provides Protection Against Alzheimer’s Disease-Induced Learning and Memory Impairments in Rats

Nan¹,

Wang²,

Zhang³

et al. 2021

DDDT

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Purpose: Recent evidence has highlighted the anti-inflammatory properties of the constituent of Green Tea Polyphenols (GTP), epigallocatechin-3-gallate (EGCG) which has been suggested to exert a neuroprotective effect on Alzheimer's disease (AD). The current study aimed to elucidate the effect of EGCG on memory function in rats with AD. Methods: AD rat models were initially established through an injection with Aβ 25-35 solution, followed by gavage with EGCG at varying doses to determine the effect of EGCG on learning and cognitive deficits in AD. Morris water maze test was conducted to evaluate the spatial memory function of the rats. Immunohistochemistry and Western blot analysis were performed to identify Tau phosphorylation. The expression of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) mRNA and protein in rat hippocampus was measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. Acetylcholinesterase (AchE) activity, Aβ1-42 expression and Ach content were all detected using enzyme-linked immunosorbent assay (ELISA). Results: EGCG intervention brought about a decrease in the escape latency period while increasing the time at the target quadrant among the AD rats. EGCG decreased the hyperphosphorylation of Tau in hippocampus. BACE1 expression and activity as well as the expression of Aβ1-42 were suppressed by EGCG. Moreover, EGCG promoted Ach content by diminishing the activity of AchE. Conclusion:The current study demonstrates that EGCG may diminish the hyperphosphorylation of the Tau protein, downregulate BACE1 and Aβ1-42 expression to improve the antioxidant system and learning and memory function of rats with AD.

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Aβ monomer induces phosphorylation of Tau at Ser‐214 through β2AR‐PKA‐JNK signaling pathway

Cited by 17 publications

References 40 publications

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

G protein‐coupled receptor kinases are associated with Alzheimer's disease pathology

Epigallocatechin-3-Gallate Provides Protection Against Alzheimer’s Disease-Induced Learning and Memory Impairments in Rats

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