New Phosphorylation Sites Identified in Hyperphosphorylated Tau (Paired Helical Filament‐Tau) from Alzheimer's Disease Brain Using Nanoelectrospray Mass Spectrometry

Hanger, Diane P.; Betts, Joanna; Loviny, Thérèse; Blackstock, Walter; Anderton, Brian H.

doi:10.1046/j.1471-4159.1998.71062465.x

Cited by 353 publications

(290 citation statements)

References 66 publications

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“…Tau has been found to be phosphorylated at over 30 serine/ threonine residues in the human brain (38,39), and approximately half of these are canonical sites for proline-directed protein kinases, including certain members of the MAP kinase, cyclin-dependent kinase and glycogen synthase kinase 3 (GSK3) families (26,40). On cultured hippocampal neurons, synthetic Aβ oligomers (sometimes called ADDLs) or AD brain extracts have been shown to induce tau phosphorylation at several epitopes (41).…”

Section: Discussionmentioning

confidence: 99%

Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration

Jin

Shepardson

Yang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

812

667

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Alzheimer disease is a major cause of cognitive failure, and a pathogenically related but more subtle process accounts for many cases of mild memory symptoms in older humans. Insoluble fibrillar plaques of amyloid β-proteins (Aβ) and neurofibrillary deposits of hyperphosphorylated tau proteins are the diagnostic lesions of AD, but their temporal mechanistic relationship has long been debated. The recent recognition that small, diffusible oligomers may be the principal bioactive form of Aβ raises the key question of whether these are sufficient to initiate cytoskeletal change and neurite degeneration. A few studies have examined the effects of oligomers of synthetic Aβ peptides of one defined length at supraphysiological concentrations, but the existence of such assemblies in the AD brain is not established. Here, we isolated Aβ dimers, the most abundant form of soluble oligomer detectable in the human brain, from the cortices of typical AD subjects and found that at subnanomolar concentrations, they first induced hyperphosphorylation of tau at AD-relevant epitopes in hippocampal neurons and then disrupted the microtubule cytoskeleton and caused neuritic degeneration, all in the absence of amyloid fibrils. Application of pure, synthetic dimers confirmed the effects of the natural AD dimers, although the former were far less potent. Knocking down endogenous tau fully prevented the neuritic changes, whereas overexpressing human tau accelerated them. Coadministering Aβ N-terminal antibodies neutralized the cytoskeletal disruption. We conclude that natural dimers isolated from the AD brain are sufficient to potently induce AD-type tau phosphorylation and then neuritic dystrophy, but passive immunotherapy mitigates this.A lzheimer disease (AD) and its harbinger, mild cognitive impairment-amnestic type, comprise the most prevalent latelife cognitive disorder in humans. The aging of the population in developed nations has led to predictions that the prevalence of Alzheimer-type dementia will rise substantially during the next few decades. Intensive research over almost 30 y has led to the hypothesis that progressive cerebral accumulation of the 42-residue amyloid β-protein (Aβ) may precipitate the synaptic dysfunction and cytoskeletal changes that underlie the symptoms of AD (1). Although insoluble amyloid plaques are one of the two neuropathological hallmarks of AD, recent studies suggest that these are in equilibrium with small, diffusible oligomers of Aβ that may serve as the principal synaptotoxic form of the protein (2).A major unresolved question about AD pathogenesis is the relationship of Aβ deposits to the other cardinal lesion of the disease, the neurofibrillary tangle. These two lesions occur together in virtually all cases of AD, but whether Aβ build-up is directly responsible for the neurofibrillary degeneration of AD is the subject of debate. Specifically, the growing experimental evidence that key features of the AD phenotype, such as dendritic spine loss, altered hippocampal synaptic plasticity, and impa...

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Section: Discussionmentioning

confidence: 99%

Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration

Jin

Shepardson

Yang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

812

667

View full text Add to dashboard Cite

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“…Tau, a substrate for several protein kinases (Singh et al, 1994;Johnson and Hartigan, 1999), is phosphorylated at over 38 serine/threonine residues in AD (MorishimaKawashima et al, 1995;Hanger et al, 1998). Given the beneficial role of ATRA in APP processing and A␤ deposition, we attempted to determine a possible role of ATRA treatment in tau hyperphosphorylation in APP/PS1 mice.…”

Section: Atra Prevents App Processing and Phosphorylation Of Both Appmentioning

confidence: 99%

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Ding¹,

et al. 2008

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Recent studies have revealed that disruption of vitamin A signaling observed in Alzheimer's disease (AD) leads to ␤-amyloid (A␤) accumulation and memory deficits in rodents. The aim of the present study was to evaluate the therapeutic effect of all-trans retinoic acid (ATRA), an active metabolite of vitamin A, on the neuropathology and deficits of spatial learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, a well established AD mouse model. Here we report a robust decrease in brain A␤ deposition and tau phosphorylation in the blinded study of APP/PS1 transgenic mice treated intraperitoneally for 8 weeks with ATRA (20 mg/kg, three times weekly, initiated when the mice were 5 months old). This was accompanied by a significant decrease in the APP phosphorylation and processing. The activity of cyclin-dependent kinase 5, a major kinase involved in both APP and tau phosphorylation, was markedly downregulated by ATRA treatment. The ATRA-treated APP/PS1 mice showed decreased activation of microglia and astrocytes, attenuated neuronal degeneration, and improved spatial learning and memory compared with the vehicle-treated APP/ PS1 mice. These results support ATRA as an effective therapeutic agent for the prevention and treatment of AD.

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“…There are six isoforms of tau protein expressed in the human brain (Goedert et al, 1989) which promote microtubule polymerization and stabilization in the nervous system (Caceres and Kosik, 1990;Drubin and Kirschner, 1986;Goedert et al, 1989;Horio and Hotani). Tau can undergo aberrant hyperphosphorylation at various sites and fail to stabilize the microtubules, contributing to neurofibrillary tangles and paired helical filaments formation (Hanger et al, 1998;Lu and Wood, 1993;Mandelkow and Mandelkow, 1998;von Linstow Roloff and Platt, 1999) which, alongside amyloid-beta (Aβ) plaques, are two prominent pathological hallmarks of AD (Braekhus, 2011;Kosik, 1991;Lee and Trojanowski, 1992). Historically, tau pathology was considered secondary to Aβ pathology.…”

Section: Introductionmentioning

confidence: 99%

Detection of the tau protein in human serum by a sensitive four-electrode electrochemical biosensor

Wang

Acha

Shah

et al. 2017

Biosensors and Bioelectronics

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This study presents a novel approach based on a four-electrode electrochemical biosensor for the detection of tau protein -one of the possible markers for the prediction of Alzheimer's disease (AD). The biosensor is based on the formation of stable antibody-antigen complexes on gold microband electrodes covered with a layer of a self-assembled monolayer and protein G. Antibodies were immobilized on the gold electrode surface in an optimal orientation by protein G interaction. Electrochemical impedance spectroscopy was used to analyze impedance change, which revealed a linear response with increasing tau concentrations. The assay is fast (<1 h for incubation and measurement) and very sensitive. The limit of quantification for the full-length 2N4R tau protein is 0.03 pM, a value unaltered when the assay was processed in bovine serum albumin or human serum. This technology could be adapted for the detection of other biomarkers to provide a multiple assay to identify AD progression in a point of care setting.

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New Phosphorylation Sites Identified in Hyperphosphorylated Tau (Paired Helical Filament‐Tau) from Alzheimer's Disease Brain Using Nanoelectrospray Mass Spectrometry

Cited by 353 publications

References 66 publications

Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration

Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Detection of the tau protein in human serum by a sensitive four-electrode electrochemical biosensor

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