curcumin and Tauopathies

The accumulation of Tau protein aggregates is a pathological hallmark of tauopathy, including chronic traumatic encephalopathy (CTE). Inhibiting Tau aggregation or disrupting preformed Tau fibrils is considered one of the rational therapeutic strategies to combat tauopathy. Previous studies reported that curcumin (Cur, a molecule of a labile natural product) and epinephrine (EP, an important neurotransmitter) could effectively inhibit the formation of Tau fibrillar aggregates and disassociate preformed fibrils. However, the underlying molecular mechanisms remain elusive. In this study, we performed multiple molecular dynamics simulations for 17.5 μs in total to investigate the influence of Cur and EP on the C-shaped Tau protofibril associated with CTE. Our simulations show that the protofibrillar pentamer is the smallest stable Tau R3-R4 protofibril. Taking the pentamer as a protofibril model, we found that both Cur and EP molecules could affect the shape of the Tau pentamer by changing the β2-β3 and β7-β8 angles, leading to a more extended structure. Cur and EP display a disruptive effect on the local β-sheets and the formation of hydrogen bonds, and thus destabilize the global protofibril structure. The contact number analysis shows that Cur has a higher binding affinity with the Tau pentamer than EP, especially in the nucleating segment PHF6. Hydrophobic, π-π and cation-π interactions together facilitate the binding of Cur and EP with the Tau pentamer. Cur exhibits stronger hydrophobic and π-π interactions with Tau than EP, and EP displays a stronger cation-π interaction. Our findings provide molecular insights into the disruptive mechanisms of the Tau R3-R4 protofibrils by curcumin and epinephrine, which may be useful for the design of effective drug candidates for the treatment of CTE.

Topics: Curcumin; Epinephrine; Humans; Molecular Dynamics Simulation; Protein Binding; tau Proteins; Tauopathies

The pathological aggregation of tau is one of the major contributing factors for several neurodegenerative tauopathies, including Alzheimer's disease. Here, we report that C1, a synthetic derivative of curcumin, strongly inhibited both the aggregation and filament formation of purified tau and protected neuroblastoma cells from the deleterious effects of the tau oligomers. Using confocal microscopy, C1 was found to reduce both the size and number of the tau droplets and increased the critical concentration of tau required for the droplet formation

Topics: Alzheimer Disease; Curcumin; Humans; Neuroblastoma; tau Proteins; Tauopathies

The pathological aggregation of tau plays an important role in Alzheimer's disease 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 o disease-relevant brain-derived tau oligomers (BDTOs). Herein, using well-characterized BDTOs, isolated from brain tissues of different tauopathies, including Alzheimer's disease, progressive supranuclear palsy, and dementia with Lewy bodies, we found that curcumin derivatives modulate the aggregation state of BDTOs by reshaping them and rescue neurons from BDTO-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.

Topics: Biopolymers; Brain; Cells, Cultured; Curcumin; Diagnosis, Differential; Humans; Neurons; Small Molecule Libraries; tau Proteins; Tauopathies

The combined fluorescent and Aβ-binding properties of the dietary spice curcumin could yield diagnostic purpose in the search for a non-invasive Aβ-biomarker for Alzheimer's disease (AD). However, evidence on the binding properties of curcumin, its conjugates and clinically used bio-available formulations to AD neuropathological hallmarks is scarce. We therefore assessed the binding properties of different curcumin forms to different neuropathological deposits in post-mortem brain tissue of cases with AD, other neurodegenerative diseases, and controls. Post mortem brain tissue was histochemically assessed for the binding of curcumin, its isoforms, conjugates and bio-available forms and compared to routinely used staining methods. For this study we included brains of early onset AD, late onset AD, primary age-related tauopathy (PART), cerebral amyloid angiopathy (CAA), frontotemporal lobar degeneration (FTLD) with tau or TAR DNA-binding protein 43 (TDP-43) inclusions, dementia with Lewy bodies (DLB), Parkinson's disease (PD) and control cases without brain pathology. We found that curcumin binds to fibrillar amyloid beta (Aβ) in plaques and CAA. It does not specifically bind to inclusions of protein aggregates in FTLD-tau cases, TDP-43, or Lewy bodies. Curcumin isoforms, conjugates and bio-available forms show affinity for the same Aβ structures. Curcumin staining overlaps with immunohistochemical detection of Aβ in fibrillar plaques and CAA, and to a lesser extent cored plaques. A weak staining of neurofibrillary tangles was observed, while other structures immunopositive for phosphorylated tau remained negative. In conclusion, curcumin, its isoforms, conjugates and bio-available forms selectively bind fibrillar Aβ in plaques and CAA in post mortem AD brain tissue. Curcumin, being a food additive with fluorescent properties, is therefore an interesting candidate for in-vivo diagnostics in AD, for example in retinal fluorescent imaging.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Anti-Inflammatory Agents, Non-Steroidal; Autopsy; Brain; Cerebral Amyloid Angiopathy; Curcumin; DNA-Binding Proteins; Female; Frontotemporal Lobar Degeneration; Humans; Male; Middle Aged; Neurofibrillary Tangles; Plaque, Amyloid; Protein Binding; Retrospective Studies; tau Proteins; Tauopathies

Intracellular inclusions of aggregated tau appear in neurons and glial cells in a range of neurodegenerative diseases known as tauopathies. Inhibition of pathological changes in tau is a therapeutic target for tauopathy. We recently synthesized a novel curcumin derivative, named Shiga-Y5, and showed that Shiga-Y5 inhibited cognitive impairment and amyloid deposition in a mouse model of Alzheimer's disease. Here we investigated whether Shiga-Y5 inhibited cognitive impairment and tau accumulation in a mouse model of tauopathy, rTg4510. The rTg4510 mouse is a bitransgenic mouse model that uses a system of responder and activator transgenes to express human four-repeat tau with the P301L mutation. This strain is obtained by crossing tetO-MAPT*P301L mouse line (on a FVB/NJ background) with CaMKII-tTA mouse line (on a C57BL/6J background). Male rTg4510 mice and wild-type mice were fed with a standard chow diet with or without Shiga-Y5 (500 ppm) for 4 months. Behavioral tests were conducted from 5.5 months of age, and the mice were sacrificed at 6 months of age. There were no significant changes in behavioral performance in rTg4510 mice fed with SY5-containing chow diet compared with rTg4510 mice fed with control chow diet. Histological and biochemical analyses also showed no significant alterations in tau accumulation by the treatment with SY5. One of noticeable finding in this study was that rTg4510 mice on a F1 female FVB/NJ x male C57BL/6J background showed more severe tau accumulation than rTg4510 mice on a F1 female C57BL/6J x male FVB/NJ background. Further studies to clarify the mechanisms underlying tau aggregation may help to develop therapeutic approaches aimed at preventing this pathological feature.

Topics: Animals; Breeding; Catechols; Cognitive Dysfunction; Curcumin; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Phenotype; tau Proteins; Tauopathies

Nuclear factor (erythroid-derived 2)-like 2 and its Caenorhabditis elegans ortholog, SKN-1, are transcription factors that have a pivotal role in the oxidative stress response, cellular homeostasis, and organismal lifespan. Similar to other defense systems, the NRF2-mediated stress response is compromised in aging and neurodegenerative diseases. Here, we report that the FDA approved drug hydralazine is a bona fide activator of the NRF2/SKN-1 signaling pathway. We demonstrate that hydralazine extends healthy lifespan (~25%) in wild type and tauopathy model C. elegans at least as effectively as other anti-aging compounds, such as curcumin and metformin. We show that hydralazine-mediated lifespan extension is SKN-1 dependent, with a mechanism most likely mimicking calorie restriction. Using both in vitro and in vivo models, we go on to demonstrate that hydralazine has neuroprotective properties against endogenous and exogenous stressors. Our data suggest that hydralazine may be a viable candidate for the treatment of age-related disorders.

Topics: Animals; Antihypertensive Agents; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cell Line, Tumor; Curcumin; Disease Models, Animal; DNA-Binding Proteins; Enzyme Inhibitors; Humans; Hydralazine; Hypoglycemic Agents; In Vitro Techniques; Longevity; Metformin; Neurons; Neuroprotective Agents; NF-E2-Related Factor 2; Stress, Physiological; Tauopathies; Transcription Factors

Tau is a key protein in the pathogenesis of various neurodegenerative diseases, which are categorized as tauopathies. Because the extent of tau pathologies is closely linked to that of neuronal loss and the clinical symptoms in Alzheimer's disease, anti-tau therapeutics, if any, could be beneficial to a broad spectrum of tauopathies. To learn more about tauopathy, we developed a novel transgenic nematode (Caenorhabditis elegans) model that expresses either wild-type or R406W tau in all the neurons. The wild-type tau-expressing worms exhibited uncoordinated movement (Unc) and neuritic abnormalities. Tau accumulated in abnormal neurites that lost microtubules. Similar abnormalities were found in the worms that expressed low levels of R406W-tau but were not in those expressing comparative levels of wild-type tau. Biochemical studies revealed that tau is aberrantly phosphorylated but forms no detergent-insoluble aggregates. Drug screening performed in these worms identified curcumin, a major phytochemical compound in turmeric, as a compound that reduces not only Unc but also the neuritic abnormalities in both wild-type and R406W tau-expressing worms. Our observations suggest that microtubule stabilization mediates the antitoxicity effect of curcumin. Curcumin is also effective in the worms expressing tau fragment, although it does not prevent the formation of tau-fragment dimers. These data indicate that curcumin improves the tau-induced neuronal dysfunction that is independent of insoluble aggregates of tau.

Topics: Animals; Animals, Genetically Modified; Caenorhabditis elegans; Curcumin; Disease Models, Animal; Gene Expression; Neurons; Protein Aggregation, Pathological; tau Proteins; Tauopathies

The mechanisms underlying Tau-related synaptic and cognitive deficits and the interrelationships between Tau species, their clearance pathways, and synaptic impairments remain poorly understood. To gain insight into these mechanisms, we examined these interrelationships in aged non-mutant genomic human Tau mice, with established Tau pathology and neuron loss. We also examined how these interrelationships changed with an intervention by feeding mice either a control diet or one containing the brain permeable beta-amyloid and Tau aggregate binding molecule curcumin. Transgene-dependent elevations in soluble and insoluble phospho-Tau monomer and soluble Tau dimers accompanied deficits in behavior, hippocampal excitatory synaptic markers, and molecular chaperones (heat shock proteins (HSPs)) involved in Tau degradation and microtubule stability. In human Tau mice but not control mice, HSP70, HSP70/HSP72, and HSP90 were reduced in membrane-enriched fractions but not in cytosolic fractions. The synaptic proteins PSD95 and NR2B were reduced in dendritic fields and redistributed into perikarya, corresponding to changes observed by immunoblot. Curcumin selectively suppressed levels of soluble Tau dimers, but not of insoluble and monomeric phospho-Tau, while correcting behavioral, synaptic, and HSP deficits. Treatment increased PSD95 co-immunoprecipitating with NR2B and, independent of transgene, increased HSPs implicated in Tau clearance. It elevated HSP90 and HSC70 without increasing HSP mRNAs; that is, without induction of the heat shock response. Instead curcumin differentially impacted HSP90 client kinases, reducing Fyn without reducing Akt. In summary, curcumin reduced soluble Tau and elevated HSPs involved in Tau clearance, showing that even after tangles have formed, Tau-dependent behavioral and synaptic deficits can be corrected.

Topics: Aged; Aged, 80 and over; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Curcumin; Disks Large Homolog 4 Protein; Female; Heat-Shock Proteins; Hippocampus; Humans; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Mice, Transgenic; Protein Multimerization; Proteolysis; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-fyn; Receptors, N-Methyl-D-Aspartate; Solubility; Synapses; tau Proteins; Tauopathies

The study aimed to characterize curcumin (CCM) (fluorescent yellow curry pigment) labeling of neuronal fibrillar tau inclusions (FTIs) in representative cases of 3 main tauopathies: Alzheimer disease (AD), progressive supranuclear palsy, and Pick disease. After identification of FTIs in hematoxylin and eosin-stained brain sections, sequential labeling and signal colocalization image analysis were used to compare CCM with thioflavine S (ThS), monoclonal antibody AT8 immunofluorescence, and Gallyas silver staining by visualizing the same FTIs. Curcumin preference for specific tau isoforms was tested with 3-repeat tau and 4-repeat tau isoform-specific immunofluorescence. Curcumin proved highly comparable to ThS and Gallyas staining in its detection of FTIs. When comparing CCM with AT8, ThS, and Gallyas staining in AD and progressive supranuclear palsy, 3 types of neuronal tau deposits were observed: nonfibrillar intracellular material labeled only with AT8, fibrillar intracellular inclusions labeled by all the methods, and fibrillar extracellular FTIs labeled with CCM, ThS, and Gallyas staining but not with AT8. Although CCM labeling overlapped with both 3-repeat tau and 4-repeat tau in AD, it did not label 3-repeat tau FTIs in Pick disease probably because of their different ultrastructural characteristics. In summary, CCM fluorescence reliably detected neuronal FTIs in AD and progressive supranuclear palsy and surpassed AT8 immunolabeling in visualizing later stages of FTIs, including ghost tangles. These results provide the basis for potential future applications of CCM binding of tau aggregates in diagnostic pathology and in vivo.

Topics: Alzheimer Disease; Benzothiazoles; Brain Diseases; Curcumin; Humans; Neurofibrillary Tangles; Neurons; Pick Disease of the Brain; Silver Staining; Supranuclear Palsy, Progressive; tau Proteins; Tauopathies; Thiazoles