Tau as a Biomarker of Neurodegenerative Diseases

Schraen, Susanna; Sergeant, Nicolas; Dhaenens, Claire‐Marie; Bombois, Stéphanie; Deramecourt, Vincent; Caillet-Boudin, Marie-Laure; Pasquier, Florence; Maurage, Claude‐Alain; Sablonnière, Bernard; Vanmechelen, Eugeen; Buée, Luc

doi:10.2217/17520363.2.4.363

Cited by 94 publications

(64 citation statements)

References 196 publications

(226 reference statements)

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“…Most frequently, these studies served to characterize post-translational modifications within tau (50 -53) and/or explored the merits of tau as a biomarker for neurodegenerative disease (54,55). Conceptually more similar to the current study were prior investigations that identified proteins that copurify with microtubules (56), explored the composition of neurofibrillar tangles (57), or investigated how the presence or absence of methylene blue alters the tau-associated proteome (58).…”

Section: Discussionmentioning

confidence: 96%

The Human Tau Interactome: Binding to the Ribonucleoproteome, and Impaired Binding of the Proline-to-Leucine Mutant at Position 301 (P301L) to Chaperones and the Proteasome

Gunawardana

Mehrabian

Wang

et al. 2015

Molecular & Cellular Proteomics

104

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The tau protein is central to the etiology of several neurodegenerative diseases, including Alzheimer's disease, a subset of frontotemporal dementias, progressive supranuclear palsy and dementia following traumatic brain injury, yet the proteins it interacts with have not been studied using a systematic discovery approach. Here we employed mild in vivo crosslinking, isobaric labeling, and tandem mass spectrometry to characterize molecular interactions of human tau in a neuroblastoma cell model. The study revealed a robust association of tau with the ribonucleoproteome, including major protein complexes involved in RNA processing and translation, and documented binding of tau to several heat shock proteins, the proteasome and microtubule-associated proteins. Follow-up experiments determined the relative contribution of cellular RNA to the tau interactome and mapped interactions to N-or C-terminal tau domains. We further document that expression of P301L mutant tau disrupts interactions of the C-terminal half of tau with heat shock proteins and the proteasome. The data are consistent with a model whereby a higher propensity of P301L mutant tau to aggregate may reflect a perturbation of its chaperone-assisted stabilization and proteasome-dependent degradation. Finally, using a global proteomics approach, we show that heterologous expression of a tau construct that lacks the C-terminal domain, including the microtubule binding domain, does not cause a discernible shift of the proteome except for a significant

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Section: Discussionmentioning

confidence: 96%

The Human Tau Interactome: Binding to the Ribonucleoproteome, and Impaired Binding of the Proline-to-Leucine Mutant at Position 301 (P301L) to Chaperones and the Proteasome

Gunawardana

Mehrabian

Wang

et al. 2015

Molecular & Cellular Proteomics

104

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“…CSF phospho-tau is thought to reflect phosphorylation states of tau in the brain [6,30,67]. While CSF p-tau181 has been widely used in CSF biomarker studies, other p-tau epitopes such as p-tau199, p-tau231, p-tau404 are also increased in AD patients [6,30,67]. A study comparing p-tau181, p-tau199, and p-tau231 using the same samples shows similar discrimination between AD and control [6,31].…”

Section: Discussionmentioning

confidence: 99%

Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network

et al. 2017

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Progranulin (PGRN) is implicated in Alzheimer’s disease (AD) as well as frontotemporal lobar degeneration. Genetic studies demonstrate an association of the common GRN rs5848 variant that results in reduced PGRN levels with increased risk for AD. However, the mechanisms by which PGRN reduction from the GRN AD risk variant or mutation exacerbates AD pathophysiology remain ill defined. Here, we show that the GRN AD risk variant has no significant effects on florbetapir positron emission tomographic amyloid imaging and cerebrospinal fluid (CSF) Aβ levels, whereas it is associated with increased CSF tau levels in human subjects of the Alzheimer’s disease neuroimaging initiative studies. Consistent with the human data, subsequent analyses using the APPswe/PS1ΔE9 (APP/PS1) mouse model of cerebral amyloidosis show that PGRN deficiency has no exacerbating effects on Aβ pathology. In contrast and unexpectedly, PGRN deficiency significantly reduces diffuse Aβ plaque growth in these APP/PS1 mice. This protective effect is due, at least in part, to enhanced microglial Aβ phagocytosis caused by PGRN deficiency-induced expression of TYROBP network genes (TNG) including an AD risk factor Trem2. PGRN-deficient APP/PS1 mice also exhibit less severe axonal dystrophy and partially improved behavior phenotypes. While PGRN deficiency reduces these amyloidosis-related phenotypes, other neuronal injury mechanisms are increased by loss of PGRN, revealing a multidimensional interaction of GRN with AD. For example, C1q complement deposition at synapses is enhanced in APP/PS1 mice lacking PGRN. Moreover, PGRN deficiency increases tau AT8 and AT180 pathologies in human P301L tau-expressing mice. These human and rodent data suggest that global PGRN reduction induces microglial TNG expression and increases AD risk by exacerbating neuronal injury and tau pathology, rather than by accelerating Aβ pathology.

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“…There are up to 85 identified phosphorylation sites on the longest Tau isoform and numerous sites are associated with Tau dysfunction and neurodegeneration (Schraen‐Maschke et al . ; Wang et al . ).…”

Section: Discussionmentioning

confidence: 99%

A novel DYRK1A (Dual specificity tyrosine phosphorylation‐regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro

Coutadeur

Benyamine

Delalonde

et al. 2015

Journal of Neurochemistry

102

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The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene is located within the Down Syndrome (DS) critical region on chromosome 21 and is implicated in the generation of Tau and amyloid pathologies that are associated with the early onset Alzheimer's Disease (AD) observed in DS. DYRK1A is also found associated with neurofibrillary tangles in sporadic AD and phosphorylates key AD players (Tau, amyloid precursor, protein, etc). Thus, DYRK1A may be an important therapeutic target to modify the course of Tau and amyloid beta (Ab) pathologies. Here, we describe EHT 5372 (methyl 9-(2,4-dichlorophenylamino) thiazolo[5,4-f]quinazoline-2-carbimidate), a novel, highly potent (IC 50 = 0.22 nM) DYRK1A inhibitor with a high degree of selectivity over 339 kinases. Models in which inhibition of DYRK1A by siRNA reduced and DYRK1A over-expression induced Tau phosphorylation or Ab production were used. EHT 5372 inhibits DYRK1A-induced Tau phosphorylation at multiple AD-relevant sites in biochemical and cellular assays. EHT 5372 also normalizes both Ab-induced Tau phosphorylation and DYRK1A-stimulated Ab production. DYRK1A is thus as a key element of Abmediated Tau hyperphosphorylation, which links Tau and amyloid pathologies. EHT 5372 and other compounds in its class warrant in vivo investigation as a novel, high-potential therapy for AD and other Tau opathies.

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Tau as a Biomarker of Neurodegenerative Diseases

Cited by 94 publications

References 196 publications

The Human Tau Interactome: Binding to the Ribonucleoproteome, and Impaired Binding of the Proline-to-Leucine Mutant at Position 301 (P301L) to Chaperones and the Proteasome

The Human Tau Interactome: Binding to the Ribonucleoproteome, and Impaired Binding of the Proline-to-Leucine Mutant at Position 301 (P301L) to Chaperones and the Proteasome

Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network

A novel DYRK1A (Dual specificity tyrosine phosphorylation‐regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro

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