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Tau is a microtubule-associated protein, which is highly expressed in the central nervous system as well as ocular neurons and stabilizes microtubule structure. It is a phospho-protein being moderately phosphorylated under physiological conditions but its abnormal hyperphosphorylation or some post-phosphorylation modifications would result in a pathogenic condition, microtubule dissociation, and aggregation. The aggregates can induce neuroinflammation and trigger some pathogenic cascades, leading to neurodegeneration. Taking these together, targeting pathogenic tau employing tau immunotherapy may be a promising therapeutic strategy in fighting with cerebral and ocular neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

• Tauopathies are neurodegenerative diseases specified by pathological tau deposits. • Phosphorylation of tau in tauopathy is analyzed by Phos-tag phosphoaffinity SDS-PAGE. • Tauopathies show disease-specific phosphorylation profiles of tau. • Site-specific phosphorylation is different among tauopathies. • Neurotoxic cis conformation of tau at pT231 is increased in AD and AGD patients. Tauopathies are neurodegenerative diseases that are characterized by pathological accumulation of tau protein. Tau is hyperphosphorylated in the brain of tauopathy patients, and this phosphorylation is proposed to play a role in disease development. However, it has been unclear whether phosphorylation is different among different tauopathies. Here, we investigated the phosphorylation states of tau in several tauopathies, including corticobasal degeneration, Pick's disease, progressive supranuclear palsy (PSP), argyrophilic grain dementia (AGD) and Alzheimer's disease (AD). Analysis of tau phosphorylation profiles using Phos-tag SDS-PAGE revealed distinct phosphorylation of tau in different tauopathies, whereas similar phosphorylation patterns were found within the same tauopathy. For PSP, we found 2 distinct phosphorylation patterns suggesting that PSP may consist of 2 different related diseases. Immunoblotting with anti-phospho-specific antibodies showed different site-specific phosphorylation in the temporal lobes of patients with different tauopathies. AD brains showed increased phosphorylation at Ser202, Thr231 and Ser235, Pick's disease brains showed increased phospho-Ser202, and AGD brains showed increased phospho-Ser396. The cis conformation of the peptide bond between phospho-Thr231 and Pro232 (cis ptau) was increased in AD and AGD. These results indicate that while tau is differently phosphorylated in tauopathies, a similar pathological mechanism may occur in AGD and AD patients. The present data provide useful information regarding tau pathology and diagnosis of tauopathies. [ABSTRACT FROM AUTHOR]

Abstract Herein, the thermodynamic parameters of tau upon interaction with NiO NPs were determined by fluorescence spectroscopy. Also, molecular docking studies were run to explore the binding affinities of NiO NPs clusters with different sizes of 30 Å and 50 Å toward tau. Also, cytotoxic activity of NiO NPs against SH-SY5Y was determined by MTT, LDH, caspase-9/3 activity, and expression of apoptotic Bax and Bcl-2 genes assays. DLS study showed that NiO solution had a good colloidal stability. Fluorescence study revealed that K SV values were 2.95 ± 0.35 × 104, 3.31 ± 0.59 × 104 and 3.92 ± 0.65 × 104 at 298 K, 310 K and 315 K, respectively. Also, ∆ G° (kJ/mol), ∆ H° (kJ/mol) and T∆ S° (kJ/mol) values were − 13.27 ± 1.57, 1.98 ± 0.14, 15.25 ± 2.01, respectively at 298 K. Theoretical studies depicted that affinity of 5O3T segment toward NiO NP (30 Å) is higher than NiO NP (50 Å) and the proportion of Lys residues are higher in the docked pose of NiO NP (30 Å)/5O3T complex than NP (50 Å)/5O3T complex. Moreover, NiO NPs demonstrated a significant increase in the mortality of SH-SY5Y cells in an apoptotic manner. This study determined that NiO NPs may mediate the formation of electrostatic interactions with tau and induction of undesired harmful effects on neurons. [ABSTRACT FROM AUTHOR]

Abstract Nickel oxide nanoparticles (NiO NPs) have been used in the biological and medical sciences. However, their toxic effects against biological systems such as nervous system have not been well studied. Therefore, the adverse effect of NiO NPs on tau structure was investigated by fluorescence and CD spectroscopic methods as well as TEM study. Also, molecular dynamic study was run to extend the experimental data. Cytotoxic activity of NiO NPs against SH-SY5Y cell was determined by trypan blue exclusion, cell morphology, ROS, and apoptosis assays. ANS, Nile red, ThT assays and electron micrograph investigation revealed that NiO NPs can increase the hydrophobic portions of tau and induce the formation of amorphous tau aggregates. Far and near CD spectroscopic methods revealed that NiO NPs can change the secondary and tertiary structure of tau, respectively. Theoretical studies depicted that NiO NPs lead to folding of tau structure. In the cellular view, NiO NPs induced significant mortality and morphological effects against SH-SY5Y cells. NiO NPs also provided a significant impact on generating intracellular ROS and apoptosis induction. This study determined that NiO NPs could mediate the induction of some undesired effects on the nervous system. Highlights • NiO NPs increased the hydrophobic portions of tau. • NiO NPs induced the formation of amorphous tau aggregates. • NiO NPs induced significant mortality and morphological effects against SH-SY5Y cells. [ABSTRACT FROM AUTHOR]

The unique proline isomerase Pin1 is pivotal for protecting against age-dependent neurodegeneration in Alzheimer's disease (AD), with its inhibition providing a molecular link between tangle and plaque pathologies. Pin1 is oxidatively modified in human AD brains, but little is known about its regulatory mechanisms and pathological significance of such Pin1 modification. In this paper, our determination of crystal structures of oxidized Pin1 reveals a series of Pin1 oxidative modifications on Cys113 in a sequential fashion. Cys113 oxidization is further confirmed by generating antibodies specifically recognizing oxidized Cys113 of Pin1. Furthermore, Pin1 oxidation on Cys113 inactivates its catalytic activity in vitro , and Ala point substitution of Cys113 inactivates the ability of Pin1 to isomerize tau as well as to promote protein turnover of tau and APP. Moreover, redox regulation affects Pin1 subcellular localization and Pin1-mediated neuronal survival in response to hypoxia treatment. Importantly, Cys113-oxidized Pin1 is significantly increased in human AD brain comparing to age-matched controls. These results not only identify a novel Pin1 oxidation site to be the critical catalytic residue Cys113, but also provide a novel oxidative regulation mechanism for inhibiting Pin1 activity in AD. These results suggest that preventing Pin1 oxidization might help to reduce the risk of AD. [ABSTRACT FROM AUTHOR]