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• The effect of age and dopamine application on working memory and LTP was studied in young and mature adult mice. • Maturation from young adult to mature adult had no effect on working memory. • Working memory increased following administration of dopamine only in mature adult subjects. • There was no difference in LTP induction and maintenance between young and mature adult mice before dopamine application. • Applying dopamine on slices from mature adults increased LTP magnitude compared slices from young adults. Normal aging in mammals is accompanied by a decline in learning and memory. Dopamine plays a vital role in regulating cognitive functions, but it declines with age: During non-pathological aging, dopamine levels, receptors, and transporters decrease. Regarding the role of the dopaminergic system's changes in old age, we examined the effect of age and applied dopamine on working memory, synaptic transmission, and long-term potentiation (LTP) induction and maintenance in young adult and mature adult mice. We employed the Y-maze spontaneous alteration test to evaluate working memory. Maturation had no observed effect on working memory performance. Interestingly, working memory performance increased following intracerebroventricular administration of dopamine only in mature adult mice. We employed evoked field potential recording (in vitro) to assess the effects of age and maturation on the long-term potentiation (LTP) induction and maintenance. There was no difference in LTP induction and maintenance between young and mature adult mice before dopamine application. However, the application of dopamine on mature adult murine slices increased LTP magnitude compared to slices from young adults. According to the obtained results, it may be concluded that hippocampal neural excitability increased in mature adult subjects, and application of dopamine abolished the difference in neural excitability among young mature and adult mature groups; which was accompanied with increment of working memory and synaptic potentiation in mature adult animals. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI), characterized by acute neurological impairment, is associated with a higher incidence of neurodegenerative diseases, particularly chronic traumatic encephalopathy (CTE), Alzheimer's disease (AD), and Parkinson's disease (PD), whose hallmarks include hyperphosphorylated tau protein. Recently, phosphorylated tau at Thr231 has been shown to exist in two distinct cis and trans conformations. Moreover, targeted elimination of cis P-tau by passive immunotherapy with an appropriate mAb that efficiently suppresses tau-mediated neurodegeneration in severe TBI mouse models has proven to be a useful tool to characterize the neurotoxic role of cis P-tau as an early driver of the tauopathy process after TBI. Here, we investigated whether active immunotherapy can develop sufficient neutralizing antibodies to specifically target and eliminate cis P-tau in the brain of TBI mouse models. First, we explored the therapeutic efficacy of two different vaccines. C57BL/6 J mice were immunized with either cis or trans P-tau conformational peptides plus adjuvant. After rmTBI in mice, we found that cis peptide administration developed a specific Ab that precisely targeted and neutralized cis P-tau, inhibited the development of neuropathology and brain dysfunction, and restored various structural and functional sequelae associated with TBI in chronic phases. In contrast, trans P-tau peptide application not only lacked neuroprotective properties, but also contributed to a number of neuropathological features, including progressive TBI-induced neuroinflammation, widespread tau-mediated neurodegeneration, worsening functional deficits, and brain atrophy. Taken together, our results suggest that active immunotherapy strategies against pathogenic cis P-tau can halt the process of tauopathy and would have profound clinical implications. [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]

Several conditions result in neurodegeneration; among which diabetes mellitus (DM) is of crucial importance. Tau (τ) malfunction is a major pathological process participating in neurodegeneration. Despite extensive considerations, the actual causative link between DM and τ abnormalities remains uncertain thus far. Phosphorylated (p)-τ at Thr–Pro motifs can exist in the two distinct cis and trans conformations. cis is neurotoxic, and is accumulated upon various stress conditions, such as nutrition depletion. We assume that pathogenic cis p-τ is the central mediator of neurodegeneration in DM, and propose why different brain areas give various responses to stress conditions. We herein juxtapose recent approaches in diabetic neurodegeneration and propose a therapeutic target to stop neuronal loss during DM. DM is a major metabolic disorder that may result in neurodegeneration. Disrupted insulin signaling pathway or glucose metabolism deficiency can induce τ hyperphosphorylation. τ is a microtubule-associated protein. It is moderately phosphorylated under physiological conditions but its hyperphosphorylation reflects pathogenicity and is a major pathological hallmark of neurodegeneration. Phosphorylated τ at Thr231 exists in the two distinct cis and trans conformations. cis p-τ is neurotoxic and drives neurodegeneration. cis p-τ is accumulated in cultured neurons upon oxidative stress as well as nutrition depletion. [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 Manganese oxide nanoparticles (Mn 2 O 3 NPs) have been widely used in the medical and biological applications. However, few studies have been undertaken to investigate the cytotoxicity of Mn 2 O 3 NPs against nervous system. Herein, we studied the toxicity of Mn 2 O 3 NPs against tau protein and neuroblastoma cells (SH-SY5Y) in vitro. Circular dichroism (CD) spectroscopy, fluorescence spectroscopy, molecular docking, and molecular dynamic studies were used to explore the conformational changes of protein. The cell-based experiments, such as viability, activation of caspases-3/9, apoptosis, and gene (Bax and Bcl-2) expression assays were performed in vitro. Spectroscopic methods and molecular dynamic studies revealed that Mn 2 O 3 NPs can fold the structure of tau toward a more packed structure. The Mn 2 O 3 NPs also decreased the cell viability in a dose-dependent manner. Indeed, caspase-3 and caspase-9 activation, Bax/Bcl-2 ratio elevation and apoptosis induction were observed after exposure of SH-SY5Y to Mn 2 O 3 NPs. In conclusion, tau folding and cytotoxicity against SH-SY5Y cells may be involved in adverse effects induced by Mn 2 O 3 NPs. [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]

Abstract The application of nanomaterials in the healthy system may induce some neurodegenerative diseases initiated by tau folding and neuronal cell death. Herein, aluminium oxide nanoparticles (Al 2 O 3 NPs) were synthesized and characterized by XRD, TEM, DLS and zeta potential investigations. Afterwards, the interaction of Al 2 O 3 NPs with tau protein was investigated by fluorescence and CD spectroscopic methods. The molecular docking and molecular dynamic were also run to explore the binding site and conformational changes of tau after interaction with Al 2 O 3 cluster. Moreover, the MTT, LDH, caspase-9/-3 and flow cytometry assays were done to explore the Al 2 O 3 NPs-induced cytotoxicity against SH-SY5Y cells. It was revealed that Al 2 O 3 NPs bind to tau protein and form a static complex and fold the structure of tau toward a more packed structure. Molecular docking and molecular dynamic investigations revealed that NPs bind to the hydrophilic residues of the tau segments and promote some marginal structural folding of tau segment. The cellular assays displayed that Al 2 O 3 NPs can elicit cell mortality through membrane leakage, caspase-9/-3 activations, and induction of both apoptosis and necrosis. This data may indicate that NPs can induce some adverse effects on the biological systems. [ABSTRACT FROM AUTHOR]

In this study, we formulated silymarin-HSA nanoplex and assayed its ability to reduce LPS-induced toxicity in vitro and in vivo. Silymarin molecules were encapsulated into HSA nanoplex and the loading efficiency and characterization of fabricated nanoplex were performed by using HPLC, TEM, SEM, DLS, FTIR analysis, and theoretical studies. Afterwards, their protective effect against LPS (20 µg/ml) -induced toxicity in SH-SY5Y cells was investigated by MTT, ROS, and apoptosis assays. For in vivo experiments, rats were pre-treated with either silymarin or silymarin -HSA nanoplex (200 mg/kg) orally for 3 days and at third day received LPS by IP at a dose of 0.5 mg/kg, 150 min before scarification followed by SOD and CAT activity assay. The formulation of silymarin-HSA nanoplex showed a spherical shape with an average diameter between 50 nm and 150 nm, hydrodynamic radius of 188.3 nm, zeta potential of −26.6 mV, and a drug loading of 97.3%. In LPS-treated cells, pretreatments with silymarin-HSA noncomplex recovered the cell viability and decreased the ROS level and corresponding apoptosis more significantly than free silymarin. In rats, it was also depicted that, silymarin-HSA noncomplex can increase the SOD and CAT activity in brain tissue at LPS-triggered oxidative stress model more significantly than the free counterpart. Therefore, nanoformulation of silymarin improved its capability to reduce LPS-induced oxidative stress by restoring cell viability and elevation of SOD and CAT activity in vitro and in vivo , respectively. In conclusion, formulation of silymarin may hold a great promise in the development of antioxidant agents. [ABSTRACT FROM AUTHOR]