Introduction of Tau Oligomers into Cortical Neurons Alters Action Potential Dynamics and Disrupts Synaptic Transmission and Plasticity

Hill, Emily; Karikari, Thomas K.; Moffat, K.; Richardson, Magnus J. E.; Wall, Mark J.

doi:10.1523/eneuro.0166-19.2019

Cited by 55 publications

(104 citation statements)

References 52 publications

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“…Recent evidence has suggested that the accumulation of tau is mediated through the spreading of misfolded tau seeds from cell-to-cell and from initial brain regions throughout the brain in a trans-synaptic pattern as the disease progresses, thus proposing a prion-like mechanism for tau protein to propagate the disease ( 19 , 68 , 69 ). Furthermore, the association of diverse tau strains with different disorders suggests that they may be partly responsible for the diverse outcomes of tauopathies, explaining how the aggregation of the same protein can cause different diseases and diverse progression and phenotypes ( 61 , 70 – 72 ).…”

Section: Discussionmentioning

confidence: 99%

Modulating disease-relevant tau oligomeric strains by small molecules

Cascio

Garcia

Montalbano

et al. 2020

Journal of Biological Chemistry

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The pathological aggregation of tau plays an important role in Alzheimer’s disease (AD) and many other related neurodegenerative diseases, collectively referred to as tauopathies. Recent evidence has demonstrated that tau oligomers, small and soluble prefibrillar aggregates, are highly toxic due to their strong ability to seed tau misfolding and propagate the pathology seen across different neurodegenerative diseases. We previously showed that novel curcumin derivatives affect preformed tau oligomer aggregation pathways by promoting the formation of more aggregated and nontoxic tau aggregates. To further investigate their therapeutic potential, we have extended our studies to disease-relevant brain-derived tau oligomers (BDTOs). Herein, using well-characterized BDTOs, isolated from brain tissues of different tauopathies, including AD, progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB), we found that curcumin derivatives modulate the aggregation state of BDTOs by reshaping them and rescue neurons from BDTOs-associated toxicity. Interestingly, compound CL3 showed an effect on the aggregation pattern of BDTOs from different tauopathies, resulting in the formation of less neurotoxic larger tau aggregates with decreased hydrophobicity and seeding propensity. Our results lay the groundwork for potential investigations of the efficacy and beneficial effects of CL3 and other promising compounds for the treatment of tauopathies. Furthermore, CL3 may aid in the development of tau imaging agent for the detection of tau oligomeric strains and differential diagnosis of the tauopathies, thus enabling earlier interventions.

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Section: Discussionmentioning

confidence: 99%

Modulating disease-relevant tau oligomeric strains by small molecules

Cascio

Garcia

Montalbano

et al. 2020

Journal of Biological Chemistry

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“…We generated the pProEx-HTa-Myc-6 × His-K18 plasmid carrying the C291R mutation (TGT > CGT, the same codon change previously reported by Marshall et al, 2015) by site-directed mutagenesis using a WT tau-K18 plasmid as a template (Karikari et al, 2017(Karikari et al, , 2019a. Protein expression and purification were achieved using our previously-characterized recombinant tau production protocols (Karikari et al, 2017(Karikari et al, , 2019aHill et al, 2019). The purified His-tagged tau-K18 constructs were used directly in functional experiments since the His-tag does not appear to affect aggregation (Huseby et al, 2019).…”

Section: Cloning Protein Expression and Purificationmentioning

confidence: 99%

The C291R Tau Variant Forms Different Types of Protofibrils

Karikari

ThOMAS

Moffat

2020

Front. Mol. Neurosci.

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Mutations in the MAPT gene can lead to disease-associated variants of tau. However, the pathological mechanisms behind these genetic tauopathies are poorly understood. Here, we characterized the aggregation stages and conformational changes of tau C291R, a recently described MAPT mutation with potential pathogenic functions. The C291R variant of the tau four-repeat domain (tau-K18; a functional fragment with increased aggregation propensity compared with the full-length protein), aggregated into a mix of granular oligomers, amorphous and annular pore-like aggregates, in nativestate and heparin-treated reactions as observed using atomic force microscopy (AFM) and negative-stained electron microscopy. On extended incubation in the native-state, tau-K18 C291R oligomers, unlike wild type (WT) tau-K18, aggregated to form protofibrils of four different phenotypes: (1) spherical annular; (2) spherical annular encapsulating granular oligomers; (3) ring-like annular but non-spherical; and (4) linear protofibrils. The ring-like tau-K18 C291R aggregates shared key properties of annular protofibrils previously described for other amyloidogenic proteins, in addition to two unique features: irregular/non-spherical-shaped annular protofibrils, and spherical protofibrils encapsulating granular oligomers. Tau-K18 C291R monomers had a circular dichroism (CD) peak at ∼210 nm compared with ∼199 nm for tau-K18 WT. These data suggest mutation-enhanced β-sheet propensity. Together, we describe the characterization of tau-K18 C291R, the first genetic mutation substituting a cysteine residue. The aggregation mechanism of tau-K18 C291R appears to involve β-sheet-rich granular oligomers which rearrange to form unique protofibrillar structures.

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“…Oligomers can be secreted from neurons via various mechanisms such as passive diffusion and exocytosis [11] as well as with neurotransmitters [12]. Other groups have shown that the propagated Tau oligomers lead to reduced long-term potentiation and increased short-term depression effect on cortical neurons, which has been partially blocked by the administration of oligomer-specific antibody [13,14]. Oligomers are the unstable species with neurotoxicity and inflammatory activity, which acts as a seed for further aggregation [13,15,16].…”

Section: Introductionmentioning

confidence: 99%

Phagocytosis of full-length Tau oligomers by Actin-remodeling of activated microglia

Das

Balmik

Chinnathambi

2020

J Neuroinflammation

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Background: Alzheimer's disease is associated with the accumulation of intracellular Tau tangles within neurons and extracellular amyloid-β plaques in the brain parenchyma, which altogether results in synaptic loss and neurodegeneration. Extracellular concentrations of oligomers and aggregated proteins initiate microglial activation and convert their state of synaptic surveillance into a destructive inflammatory state. Although Tau oligomers have fleeting nature, they were shown to mediate neurotoxicity and microglial pro-inflammation. Due to the instability of oligomers, in vitro experiments become challenging, and hence, the stability of the full-length Tau oligomers is a major concern. Methods: In this study, we have prepared and stabilized hTau40 WT oligomers, which were purified by size-exclusion chromatography. The formation of the oligomers was confirmed by western blot, thioflavin-S, 8-anilinonaphthaalene-1sulfonic acid fluorescence, and circular dichroism spectroscopy, which determine the intermolecular cross-β sheet structure and hydrophobicity. The efficiency of N9 microglial cells to phagocytose hTau40 WT oligomer and subsequent microglial activation was studied by immunofluorescence microscopy with apotome. The one-way ANOVA was performed for the statistical analysis of fluorometric assay and microscopic analysis. Results: Full-length Tau oligomers were detected in heterogeneous globular structures ranging from 5 to 50 nm as observed by high-resolution transmission electron microscopy, which was further characterized by oligomer-specific A11 antibody. Immunocytochemistry studies for oligomer treatment were evidenced with A11 + Iba1 high microglia, suggesting that the phagocytosis of extracellular Tau oligomers leads to microglial activation. Also, the microglia were observed with remodeled filopodia-like actin structures upon the exposure of oligomers and aggregated Tau. Conclusion: The peri-membrane polymerization of actin filament and co-localization of Iba1 relate to the microglial movements for phagocytosis. Here, these findings suggest that microglia modified actin cytoskeleton for phagocytosis and rapid clearance of Tau oligomers in Alzheimer's disease condition.

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Introduction of Tau Oligomers into Cortical Neurons Alters Action Potential Dynamics and Disrupts Synaptic Transmission and Plasticity

Cited by 55 publications

References 52 publications

Modulating disease-relevant tau oligomeric strains by small molecules

Modulating disease-relevant tau oligomeric strains by small molecules

The C291R Tau Variant Forms Different Types of Protofibrils

Phagocytosis of full-length Tau oligomers by Actin-remodeling of activated microglia

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