Unraveling the Mechanism of Tau Protein Aggregation in Presence of Zinc Ion: The Earliest Step of Tau Aggregation

: Major research in Alzheimer’s disease (AD) related to disease-modifying agents is concentrated on pharmacological approaches related to diagnostic markers, neurofibrillary tangles and amyloid plaques. Although most studies focus on anti-amyloid strategies, investigations on tau protein have produced significant advances in the modulation of the pathophysiology of several neurodegenerative diseases. Since the discovery of phenothiazines as tau protein aggregation inhibitors (TAGIs), many additional small molecule inhibitors have been discovered and characterized in biological model systems, which exert their interaction effects by covalent and noncovalent means. In this paper, we summarize the latest advances in the discovery and development of tau aggregation inhibitors using a specialized approach in their chemical classes. The design of new TAGIs and their encouraging use in in vivo and clinical trials support their potential therapeutic use in AD.

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Microfluidic Protein Imaging Platform: Study of Tau Protein Aggregation and Alzheimer’s Drug Response

Bioengineering ◽

10.3390/bioengineering7040162 ◽

2020 ◽

Vol 7 (4) ◽

pp. 162

Author(s):

Shubha Jain ◽

Sarpras Swain ◽

Lopamudra Das ◽

Sarita Swain ◽

Lopamudra Giri ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Aggregation ◽

Tau Protein ◽

Drug Response ◽

Drug Evaluation ◽

Confocal Imaging ◽

Tau Imaging ◽

On Chip ◽

Tau Aggregation

Tau protein aggregation is identified as one of the key phenomena associated with the onset and progression of Alzheimer’s disease. In the present study, we performed on-chip confocal imaging of tau protein aggregation and tau–drug interactions using a spiral-shaped passive micromixing platform. Numerical simulations and experiments were performed in order to validate the performance of the micromixer design. We performed molecular modeling of adenosine triphosphate (ATP)-induced tau aggregation in order to successfully validate the concept of helical tau filament formation. Tau aggregation and native tau restoration were realized using an immunofluorescence antibody assay. The dose–response behavior of an Alzheimer’s drug, methylthioninium chloride (MTC), was monitored on-chip for defining the optimum concentration of the drug. The proposed device was tested for reliability and repeatability of on-chip tau imaging. The amount of the tau protein sample used in our experiments was significantly less than the usage for conventional techniques, and the whole protein–drug assay was realized in less than two hours. We identified that intensity-based tau imaging could be used to study Alzheimer’s drug response. In addition, it was demonstrated that cell-free, microfluidic tau protein assays could be used as potential on-chip drug evaluation tools for Alzheimer’s disease.

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Preferential tau aggregation in von Economo neurons and fork cells in frontotemporal lobar degeneration with specific MAPT variants

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0809-0 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 3

Author(s):

Li-Chun Lin ◽

Alissa L. Nana ◽

Mackenzie Hepker ◽

Ji-Hye Lee Hwang ◽

Stephanie E. Gaus ◽

...

Keyword(s):

Protein Aggregation ◽

Tau Protein ◽

Frontotemporal Lobar Degeneration ◽

Brain Regions ◽

Anterior Cingulate ◽

Gene Encoding ◽

Von Economo Neurons ◽

Pathogenic Variants ◽

Tau Aggregation ◽

Fork Cells

Abstract Tau aggregation is a hallmark feature in a subset of patients with frontotemporal dementia (FTD). Early and selective loss of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices (ACC) is observed in patients with sporadic behavioral variant FTD (bvFTD) due to frontotemporal lobar degeneration (FTLD), including FTLD with tau inclusions (FTLD-tau). Recently, we further showed that these specialized neurons show preferential aggregation of TDP-43 in FTLD-TDP. Whether VENs and fork cells are prone to tau accumulation in FTLD-tau remains unclear, and no previous studies of these neurons have focused on patients with pathogenic variants in the gene encoding microtubule-associated protein tau (FTLD-tau/MAPT). Here, we examined regional profiles of tau aggregation and neurodegeneration in 40 brain regions in 8 patients with FTLD-tau/MAPT and 7 with Pick’s disease (PiD), a sporadic form of FTLD-tau that often presents with bvFTD. We further qualitatively assessed the cellular patterns of frontoinsular tau aggregation in FTLD-tau/MAPT using antibodies specific for tau hyperphosphorylation, acetylation, or conformational change. ACC and mid-insula were among the regions most affected by neurodegeneration and tau aggregation in FTLD-tau/MAPT and PiD. In these two forms of FTLD-tau, severity of regional neurodegeneration and tau protein aggregation were highly correlated across regions. In FTLD-tau/MAPT, VENs and fork cells showed disproportionate tau protein aggregation in patients with V337 M, A152T, and IVS10 + 16 variants, but not in patients with the P301L variant. As seen in FTLD-TDP, our data suggest that VENs and fork cells represent preferentially vulnerable neuron types in most, but not all of the MAPT variants we studied.

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Ring-opened aminothienopyridazines as novel tau aggregation inhibitors

MedChemComm ◽

10.1039/c6md00306k ◽

2017 ◽

Vol 8 (6) ◽

pp. 1275-1282 ◽

Cited By ~ 6

Author(s):

M. Moir ◽

S. W. Chua ◽

T. Reekie ◽

A. D. Martin ◽

A. Ittner ◽

...

Keyword(s):

Protein Aggregation ◽

Tau Protein ◽

Aggregation Inhibitors ◽

Tau Aggregation

Simplified aminothienopyridazine analogues were synthesised and their inhibition of tau protein aggregation assessed.

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Effects of resveratrol and morin on insoluble tau in tau transgenic mice

Translational Neuroscience ◽

10.1515/tnsci-2018-0010 ◽

2018 ◽

Vol 9 (1) ◽

pp. 54-60 ◽

Cited By ~ 8

Author(s):

Kwun Chung Yu ◽

Ping Kwan ◽

Stanley K.K. Cheung ◽

Amy Ho ◽

Larry Baum

Keyword(s):

Transgenic Mice ◽

Motor Function ◽

Tau Protein ◽

Late Stage ◽

Animal Studies ◽

Paired Helical Filaments ◽

Hyperphosphorylated Tau ◽

Total Tau ◽

Tau Aggregation ◽

Do So

Abstract Tauopathies are neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD), in which tau protein aggregates within neurons. An effective treatment is lacking and is urgently needed. We evaluated two structurally similar natural compounds, morin and resveratrol, for treating tauopathy in JNPL3 P301L mutant human tau overexpressing mice. Rotarod tests were performed to determine effects on motor function. After treatment from age 11 to 14 months, brains of 26 mice were collected to quantify aggregated hyperphosphorylated tau by Thioflavin T and immunohistochemistry (IHC) and to quantify total tau (HT7 antibody) and hyperphosphorylated tau (AT8 antibody) in homogenates and a fraction enriched for paired helical filaments. Resveratrol reduced the level of total hyperphosphorylated tau in IHC sections (p=0.036), and morin exhibited a tendency to do so (p=0.29), while the two drugs tended to increase the proportion of solubilizable tau that was hyperphosphorylated, as detected in blots. Neither resveratrol nor morin affected motor function. One explanation of these results is that the drugs might interrupt a late stage in tau aggregation, after small aggregates have formed but before further aggregation has occurred. Further animal studies would be informative to explore the possible efficacy of morin or resveratrol for treating tauopathies.

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Tau protein aggregation in the frontal and entorhinal cortices as a function of aging

Developmental Brain Research ◽

10.1016/j.devbrainres.2005.02.004 ◽

2005 ◽

Vol 156 (2) ◽

pp. 127-138 ◽

Cited By ~ 31

Author(s):

Wencheng Yang ◽

Lee Cyn Ang ◽

Michael J. Strong

Keyword(s):

Protein Aggregation ◽

Tau Protein

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An in vitro study of the role of docosahexaenoic acid in human tau protein aggregation

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2016.1248489 ◽

2016 ◽

Vol 35 (14) ◽

pp. 3176-3181

Author(s):

Elham Sadat Mostafavi ◽

Mohammad Ali Nasiri Khalili ◽

Sirus Khodadadi ◽

Gholam Hossein Riazi

Keyword(s):

Docosahexaenoic Acid ◽

Protein Aggregation ◽

Tau Protein ◽

In Vitro Study ◽

Vitro Study

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Dextran sulphate-induced tau assemblies cause endogenous tau aggregation and propagation in wild-type mice

Brain Communications ◽

10.1093/braincomms/fcaa091 ◽

2020 ◽

Vol 2 (2) ◽

Author(s):

Masami Masuda-Suzukake ◽

Genjiro Suzuki ◽

Masato Hosokawa ◽

Takashi Nonaka ◽

Michel Goedert ◽

...

Keyword(s):

Transgenic Mice ◽

Tau Protein ◽

Guanidine Hydrochloride ◽

Intracerebral Injection ◽

Dextran Sulphate ◽

Wild Type ◽

Synthetic Filament ◽

Biochemical Analyses ◽

Tau Aggregation

Abstract Accumulation of assembled tau protein in the central nervous system is characteristic of Alzheimer’s disease and several other neurodegenerative diseases, called tauopathies. Recent studies have revealed that propagation of assembled tau is key to understanding the pathological mechanisms of these diseases. Mouse models of tau propagation are established by injecting human-derived tau seeds intracerebrally; nevertheless, these have a limitation in terms of regulation of availability. To date, no study has shown that synthetic assembled tau induce tau propagation in non-transgenic mice. Here we confirm that dextran sulphate, a sulphated glycosaminoglycan, induces the assembly of recombinant tau protein into filaments in vitro. As compared to tau filaments induced by heparin, those induced by dextran sulphate showed higher thioflavin T fluorescence and lower resistance to guanidine hydrochloride, which suggests that the two types of filaments have distinct conformational features. Unlike other synthetic filament seeds, intracerebral injection of dextran sulphate-induced assemblies of recombinant tau caused aggregation of endogenous murine tau in wild-type mice. AT8-positive tau was present at the injection site 1 month after injection, from where it spread to anatomically connected regions. Induced tau assemblies were also stained by anti-tau antibodies AT100, AT180, 12E8, PHF1, anti-pS396 and anti-pS422. They were thioflavin- and Gallyas-Braak silver-positive, indicative of amyloid. In biochemical analyses, accumulated sarkosyl-insoluble and hyperphosphorylated tau was observed in the injected mice. In conclusion, we revealed that intracerebral injection of synthetic full-length wild-type tau seeds prepared in the presence of dextran sulphate caused tau propagation in non-transgenic mice. These findings establish that propagation of tau assemblies does not require tau to be either mutant and/or overexpressed.

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Pharmacological Modulators of Tau Aggregation and Spreading

Brain Sciences ◽

10.3390/brainsci10110858 ◽

2020 ◽

Vol 10 (11) ◽

pp. 858

Author(s):

Antonio Dominguez-Meijide ◽

Eftychia Vasili ◽

Tiago Fleming Outeiro

Keyword(s):

Tau Protein ◽

Neurodegenerative Disorders ◽

Molecular Mechanisms ◽

Mechanisms Of Action ◽

Tau Aggregation ◽

The Brain ◽

Pharmacological Modulators

Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates composed of abnormal tau protein in the brain. Additionally, misfolded forms of tau can propagate from cell to cell and throughout the brain. This process is thought to lead to the templated misfolding of the native forms of tau, and thereby, to the formation of newer toxic aggregates, thereby propagating the disease. Therefore, modulation of the processes that lead to tau aggregation and spreading is of utmost importance in the fight against tauopathies. In recent years, several molecules have been developed for the modulation of tau aggregation and spreading. In this review, we discuss the processes of tau aggregation and spreading and highlight selected chemicals developed for the modulation of these processes, their usefulness, and putative mechanisms of action. Ultimately, a stronger understanding of the molecular mechanisms involved, and the properties of the substances developed to modulate them, will lead to the development of safer and better strategies for the treatment of tauopathies.

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