Tau Protein Expression Research Articles

Neuroprotective Effect of Fisetin Against Amyloid-Beta-Induced Cognitive/Synaptic Dysfunction, Neuroinflammation, and Neurodegeneration in Adult Mice.

Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disease and is characterized pathologically by the accumulation of amyloid beta (Aβ) and the hyperphosphorylation of tau proteins in the brain. The deposition of Aβ aggregates triggers synaptic dysfunction, hyperphosphorylation of tau, and neurodegeneration, which lead to cognitive disorders. Here, we investigated the neuroprotective effect of fisetin in the Aβ1-42 mouse model of AD. Single intracerebroventricular injections of Aβ1-42 (3μl/5min/mouse) markedly induced memory/synaptic deficits, neuroinflammation, and neurodegeneration. Intraperitoneal injections of fisetin at a dose of 20mg/kg/day for 2weeks starting 24h after Aβ1-42 injection significantly decreased the Aβ1-42-induced accumulation of Aβ, BACE-1 expression, and hyperphosphorylation of tau protein at serine 413. Fisetin treatment also markedly reversed Aβ1-42-induced synaptic dysfunction by increasing the levels of both presynaptic (SYN and SNAP-25) and postsynaptic proteins (PSD-95, SNAP-23, p-GluR1 (Ser 845), p-CREB (Ser 133) and p-CAMKII (Thr 286) and ultimately improved mouse memory, as observed in the Morris water maze test. Fisetin significantly activated p-PI3K, p-Akt (Ser 473), and p-GSK3β (Ser 9) expression in Aβ1-42-treated mice. Moreover, fisetin prevented neuroinflammation by suppressing various activated neuroinflammatory mediators and gliosis; it also suppressed the apoptotic neurodegeneration triggered by Aβ1-42 injections in the mouse hippocampus. Fluorojade-B and immunohistochemical staining for caspase-3 revealed that fisetin prevented neurodegeneration in Aβ1-42-treated mice. Our results suggest that fisetin has a potent neuroprotective effect against Aβ1-42-induced neurotoxicity. These results demonstrate that polyphenolic flavonoids such as fisetin could be a beneficial, effective and safe neuroprotective agent for preventing neurological disorders such as AD.

Tau-Driven Neuronal and Neurotrophic Dysfunction in a Mouse Model of Early Tauopathy.

This work highlights the potential molecular mechanisms by which initial tauopathy induces neuronal dysfunction. Combining clinically used electrophysiological techniques (i.e., electroretinography) and molecular analyses, this work shows that in a relevant model of early tauopathy, the retina of the P301S mutant human tau transgenic mouse, mild tau pathology results in functional changes of neuronal activity, likely due to selective impairment of brain-derived neurotrophic factor signaling via its receptor, TrkB. These findings may have important translational implications for early diagnosis in a subset of Alzheimer's disease patients with early visual symptoms and emphasize the need to clarify the pathophysiological changes associated with distinct tauopathy stages to support informed therapeutic decisions and guide drug discovery.

Multiple signaling factors and drugs alleviate neuronal death induced by expression of human and zebrafish tau proteins in vivo.

BackgroundThe axonal tau protein is a tubulin-binding protein, which plays important roles in the formation and stability of the microtubule. Mutations in the tau gene are associated with familial forms of frontotemporal dementia with Parkinsonism linked to chromosome-17 (FTDP-17). Paired helical filaments of tau and extracellular plaques containing beta-amyloid are found in the brain of Alzheimer’s disease (AD) patients.ResultsTransgenic models, including those of zebrafish, have been employed to elucidate the mechanisms by which tau protein causes neurodegeneration. In this study, a transient expression system was established to express GFP fusion proteins of zebrafish and human tau under the control of a neuron-specific HuC promoter. Approximately ten neuronal cells expressing tau-GFP in zebrafish embryos were directly imaged and traced by time-lapse recording, in order to evaluate the neurotoxicity induced by tau-GFP proteins. Expression of tau-GFP was observed to cause high levels of neuronal death. However, multiple signaling factors, such as Bcl2-L1, Nrf2, and GDNF, were found to effectively protect neuronal cells expressing tau-GFP from death. Treatment with chemical compounds that exert anti-oxidative or neurotrophic effects also resulted in a similar protective effect and maintained human tau-GFP protein in a phosphorylated state, as detected by antibodies pT212 and AT8.ConclusionsThe novel finding of this study is that we established an expression system expressing tau-GFP in zebrafish embryos were directly imaged and traced by time-lapse recording to evaluate the neurotoxicity induced by tau-GFP proteins. This system may serve as an efficient in vivo imaging platform for the discovery of novel drugs against tauopathy.

Effects of microtubule-associated protein tau expression on neural stem cell migration after spinal cord injury.

Our preliminary proteomics analysis suggested that expression of microtubule-associated protein tau is elevated in the spinal cord after injury. Therefore, the first aim of the present study was to examine tau expression in the injured spinal cord. The second aim was to determine whether tau can regulate neural stem cell migration, a critical factor in the successful treatment of spinal cord injury. We established rat models of spinal cord injury and injected them with mouse hippocampal neural stem cells through the tail vein. We used immunohistochemistry to show that the expression of tau protein and the number of migrated neural stem cells were markedly increased in the injured spinal cord. Furthermore, using a Transwell assay, we showed that neural stem cell migration was not affected by an elevated tau concentration in the outer chamber, but it was decreased by changes in intracellular tau phosphorylation state. These results demonstrate that neural stem cells have targeted migration capability at the site of injury, and that although tau is not a chemokine for targeted migration of neural stem cells, intracellular tau phosphorylation/dephosphorylation can inhibit cell migration.

Cognitive function and biomarkers after traumatic brain injury: protocol for a prospective inception cohort study

Background: Traumatic brain injury is a high-incidence condition that can cause severe cognitive impairment. At present, functional magnetic resonance imaging is used to analyze changes in brain function and network connectivity at different stages of injury. In addition, tau protein expression in nerve cells may reflect cognitive function. However, the combined use of functional magnetic resonance imaging and tau measurement to assess cognitive function following traumatic brain injury has not yet been investigated. Methods/Design: A prospective inception cohort study will be performed at the 101 st Hospital of PLA, Wuxi, China. We will conduct a follow-up visit in 100 patients with traumatic brain injury. Cognitive function will be assessed within 24 hours of injury and 0.5, 1, and 2 years after injury. Primary outcomes will be the Montreal Cognitive Assessment score, functional magnetic resonance imaging results, and tau protein level in the cerebrospinal fluid. Secondary outcomes will include Mini-Mental State Examination Scale and Hamilton Depression Scale scores. We will assess cognitive function in patients with traumatic brain injury and analyze its correlation with functional imaging indexes and tau levels in the cerebrospinal fluid. Discussion: This trial has been designed to determine whether functional imaging indexes and tau level in the cerebrospinal fluid can predict recovery of cognitive function in patients with traumatic brain injury. It will provide objective evidence for the clinical prevention and treatment of cognitive dysfunction following traumatic brain injury. Trial registration: This trial was registered at Chinese Clinical Trial Registry (registration number: ChiCTR-OOC-16008574) on 31 May 2016. Ethics: Approved by the Ethics Committee of the 101 st Hospital of PLA, China (approval number: L2016002), the study protocol will be performed in accordance with the guidelines of the Declaration of Helsinki , formulated by the World Medical Association. Informed consent: Written informed consent will be obtained from participants or their guardians.

Changes in microtubule-associated protein tau during peripheral nerve injury and regeneration.

Tau, a primary component of microtubule-associated protein, promotes microtubule assembly and/or disassembly and maintains the stability of the microtubule structure. Although the importance of tau in neurodegenerative diseases has been well demonstrated, whether tau is involved in peripheral nerve regeneration remains unknown. In the current study, we obtained sciatic nerve tissue from adult rats 0, 1, 4, 7, and 14 days after sciatic nerve crush and examined tau mRNA and protein expression levels and the location of tau in the sciatic nerve following peripheral nerve injury. The results from our quantitative reverse transcription polymerase chain reaction analysis showed that compared with the uninjured control sciatic nerve, mRNA expression levels for both tau and tau tubulin kinase 1, a serine/threonine kinase that regulates tau phosphorylation, were decreased following peripheral nerve injury. Our western blot assay results suggested that the protein expression levels of tau and phosphorylated tau initially decreased 1 day post nerve injury but then gradually increased. The results of our immunohistochemical labeling showed that the location of tau protein was not altered by nerve injury. Thus, these results showed that the expression of tau was changed following sciatic nerve crush, suggesting that tau may be involved in peripheral nerve repair and regeneration.

Expression of Tau Protein and Tau mRNA in gastric carcinoma

Aims and Objectives: To provide theoretical basis for the gastric carcinoma pathogenesis and the clinical targeted therapy. Materials and Methods: We detected the expression of Tau protein and Tau mRNA in 60 cases of gastric carcinoma tissues (observation group) and 10 cases of normal gastric tissues (control group). Immunohistochemisty was adopted to detect the expression of Tau protein in normal and carcinomatous gastric tissue. Tau mRNA was detected by RT-PCR in normal and carcinomatous gastric tissue. To analyse the experimental data combined clinical pathology with statistics. Results: The expression of Tau protein in carcinomatous gastric tissue was higher than that in normal gastric tissue (P<0.05). The expression of Tau protein and Tau mRNA in well differentiated and moderately differentiated was lower than that in poorly differentiated gastric carcinoma (P<0.05). The expression of Tau protein and Tau mRNA in gastric carcinoma without lymph node metastasis was lower than that in gastric carcinoma with lymph node metastasis (P<0.05). The expression of Tau mRNA in carcinomatous gastric tissue was higher than that in normal gastric tissue (P<0.05).Conclusion: Tau protein and Tau mRNA were significant differences between normal gastric tissue and gastric carcinoma, also were concerned with differentiation in grade and lymph node metastasis of gastric carcinoma.Asian Journal of Medical Sciences Vol.7(1) 2015 20-23

Role of adenosine A1receptors in hippocampal neurons in cognitive dysfunction caused by isoflurane anesthesia in aged mice

Objective To evaluate the role of adenosine A1 receptors in hippocampal neurons in the cognitive dysfunction caused by isoflurane anesthesia in aged mice. Methods Sixteen male adenosine A1 receptor gene knockout homozygote mice(gene knockout mice)and 16 male wild-type mice, aged 18-22 months, weighing 27-32 g, were studied.Each type of mice was randomly divided into 2 groups(n=8 each)using a random number table: control group(group C)and isoflurane anesthesia group(group I). Mice inhaled 1.4% isoflurane in 100% O2 for 2 h in group I, and 100% O2 for 2 h in group C. All the mice underwent Morris water maze test at 24 h after isoflurane or O2 inhalation.After the test, the mice were sacrificed and the hippocampal tissues were harvested to determine the number of β-amyloid1-42(Aβ1-42)plaques(using immunohistochemistry)and expression of phosphorylated tau(p-tau)protein, and 2B subunit-containing N-methyl-D-aspartate receptors(NR2B)(by Western blot analysis). Results Compared with group C of wild type mice, the escape latency was significantly prolonged, the number of Aβ1-42 plaques was enlarged, the expression of p-tau protein was up-regulated, and the expression of NR2B was down-regulated in group I of wild type mice.Compared with group I of wild type mice, the escape latency was significantly shortened, the number of Aβ1-42 plaques was decreased, the expression of p-tau protein was down-regulated, and the expression of NR2B was up-regulated in group I of gene knockout mice.There was no significant difference in the parameters mentioned above between group I and group C of gene knockout mice. Conclusion Adenosine A1receptors in hippocampal neurons mediate isoflurane anesthesia-induced cognitive dysfunction in aged mice, and the mechanism may be related to promotion of deposition of Aβ, phosphorylation of tau protein and inhibition of activities of NR2B. Key words: Receptor, adenosine A1; Hippocampus; Neurons; Isoflurane; Cognition disorders; Aged

Asynchronous therapy targeting Nogo-A enhances neurobehavioral recovery by reducing neuronal loss and promoting neurite outgrowth after cerebral ischemia in mice

Therapeutics targeting the Nogo-A signal pathway hold promise to promote recovery following brain injury. Based on the temporal characteristics of Nogo-A expression in the process of cerebral ischemia and reperfusion, we tested a novel asynchronous treatment, in which TAT-M9 was used in the early stage to decrease neuronal loss, and TAT-NEP1-40 was used in the delayed stage to promote neurite outgrowth after bilateral common carotid artery occlusion (BCCAO) in mice. Both TAT-M9 and TAT-NEP1-40 were efficiently delivered into the brains of mice by intraperitoneal injection. TAT-M9 treatment promoted neuron survival and inhibited neuronal apoptosis. Asynchronous therapy with TAT-M9 and TAT-NEP1-40 increased the expression of Tau, GAP43 and MAP-2 proteins, and enhanced short-term and long-term cognitive functions. In conclusion, the asynchronous treatment had a long-term neuroprotective effect, which reduced neurologic injury and apoptosis, promoted neurite outgrowth and enhanced functional recovery after ischemia. It suggests that this asynchronous treatment could be a promising therapy for cerebral ischemia in humans.

Potential natural products for Alzheimer's disease: targeted search using the internal ribosome entry site of tau and amyloid-β precursor protein.

Overexpression of the amyloid precursor protein (APP) and the hyperphosphorylation of the tau protein are vital in the understanding of the cause of Alzheimer’s disease (AD). As a consequence, regulation of the expression of both APP and tau proteins is one important approach in combating AD. The APP and tau proteins can be targeted at the levels of transcription, translation and protein structural integrity. This paper reports the utilization of a bi-cistronic vector containing either APP or tau internal ribosome entry site (IRES) elements flanked by β-galactosidase gene (cap-dependent) and secreted alkaline phosphatase (SEAP) (cap-independent) to discern the mechanism of action of memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist. Results indicate that memantine could reduce the activity of both the APP and tau IRES at a concentration of ~10 μM (monitored by SEAP activity) without interfering with the cap-dependent translation as monitored by the β-galactosidase assay. Western blot analysis of the tau protein in neuroblastoma (N2A) and rat hippocampal cells confirmed the halting of the expression of the tau proteins. We also employed this approach to identify a preparation named NB34, extracts of Boussingaultia baselloides (madeira-vine) fermented with Lactobacillus spp., which can function similarly to memantine in both IRES of APP and Tau. The water maze test demonstrated that NB34 could improve the spatial memory of a high fat diet induced neurodegeneration in apolipoprotein E-knockout (ApoE−/−) mice. These results revealed that the bi-cistronic vector provided a simple, and effective platform in screening and establishing the mechanistic action of potential compounds for the treatment and management of AD.

Predictive value of microtubule-associated protein Tau in patients with recurrent and metastatic breast cancer treated with taxane-containing palliative chemotherapy.

Tau is a member of microtubule-associated proteins (MAPs) and expressed in normal breast epithelium and breast cancer cells. Tau expression levels in early breast cancer were correlated with the responsiveness of taxane-containing chemotherapy. However, it is unknown whether Tau contributes to breast cancer progression. Herein, Tau expression in recurrent and metastatic breast cancer (RMBC) and its predictive significance in taxane-containing palliative chemotherapy were investigated. Immunohistochemical (IHC) staining was conducted to detect Tau protein expression levels in biopsies from 285 patients with RMBC, and the correlation between Tau expression and sensitivity to taxane was evaluated. One hundred twenty-one (42.46 %, 121/285) patients were Tau positive in their tumor. One hundred ninety-four (68.07 %, 194/285) patients were effective clinical remission, which evaluated with response evaluation criteria in solid tumors (RECIST) criteria. In this group, 141 (85.98 %, 141/194) patients were Tau negative. We further analyzed the correlation between Tau expression and clinicopathological characteristics. Tau expression was positively correlated to estrogen receptor (ER) status. Multivariate logistic regression analysis showed that Tau expression significantly differentiated patients with effective response to treatment (95 % confidence interval (CI): 4.230-13.88, P < 0.01). Tau expression was identified as an independent factor to predict the sensitivity of tumors to taxane-containing palliative chemotherapy in RMBC, suggesting that Tau expression in RMBC may serve as a clinical predictor for taxane-containing palliative chemotherapy.

Titanium dioxide nanoparticles alter cellular morphology via disturbing the microtubule dynamics.

Titanium dioxide (TiO2) nanoparticles (NPs) have been widely used in our daily lives, for example, in the areas of sunscreens, cosmetics, toothpastes, food products, and nanomedical reagents. Recently, increasing concern has been raised about their neurotoxicity, but the mechanisms underlying such toxic effects are still unknown. In this work, we employed a human neuroblastoma cell line (SH-SY5Y) to study the effects of TiO2 NPs on neurological systems. Our results showed that TiO2 NPs did not affect cell viability but induced noticeable morphological changes until 100 μg ml(-1). Immunofluorescence detection showed disorder, disruption, retraction, and decreased intensity of the microtubules after TiO2 NPs treatment. Both α and β tubule expressions did not change in the TiO2 NP-treated group, but the percentage of soluble tubules was increased. A microtubule dynamic study in living cells indicated that TiO2 NPs caused a lower growth rate and a higher shortening rate of microtubules as well as shortened lifetimes of de novo microtubules. TiO2 NPs did not cause changes in the expression and phosphorylation state of tau proteins, but a tau-TiO2 NP interaction was observed. TiO2 NPs could interact with tubule heterodimers, microtubules and tau proteins, which led to the instability of microtubules, thus contributing to the neurotoxicity of TiO2 NPs.

Tolfenamic acid reduces tau and CDK5 levels: implications for dementia and tauopathies.

Tau and its aggregates are linked to the pathology of Alzheimer's disease (AD) and other tauopathies and, therefore, are explored as therapeutic targets for such disorders. Tau belongs to a family of microtubule-associated proteins that promote microtubule assembly. When hyperphosphorylated, tau becomes prone to forming aggregates. Increased brain levels of hyperphosphorylated tau correlate with dementia. Specificity protein 1 (Sp1), a transcription factor elevated in AD, is responsible for the transcription of AD-related proteins including the amyloid precursor protein, tau, and its cyclin-dependent kinase-5 (CDK5) activators. Tolfenamic acid promotes the degradation of Sp1, our previous studies demonstrated its ability to down-regulate transcriptional targets of Sp1 like amyloid precursor protein and reduce amyloid beta (Aβ), the main component of AD plaques. In this study, we administered tolfenamic acid daily to hemizygous R1.40 transgenic mice for 34 days, and examined tau and CDK5 gene and protein expression within the brain. Our results demonstrate that tolfenamic acid lowers tau mRNA and protein, as well as the levels of its phosphorylated form and CDK5. Thus, we present a drug candidate that inhibits the transcription of multiple major intermediates in AD pathology, thereby helping uncover a new mechanism-based approach for targeting AD. A new approach for targeting Alzheimer's disease through a transcriptional based mechanism is presented. Tolfenamic acid lowers the levels of tau, which forms pathological aggregates in Alzheimer's disease and other tauopathies, by promoting the degradation of the transcription factor specificity protein 1 which regulates tau transcription.

Tau silencing by siRNA in the P301S mouse model of tauopathy.

Suppression of tau protein expression has been shown to improve behavioral deficits in mouse models of tauopathies, offering an attractive therapeutic approach. Experimentally this had been achieved by switching off the promoters controlling the transgenic human tau gene (MAPT), which is not possible in human patients. The aim of the present study was therefore to evaluate the effectiveness of small interfering RNAs (siRNAs) and their cerebral delivery to suppress human tau expression in vivo, which might be a therapeutic option for human tauopathies. We used primary cortical neurons of transgenic mice expressing P301S-mutated human tau and Lund human mesencephalic (LUHMES) cells to validate the suppressive effect of siRNA in vitro. For measuring the effect in vivo, we stereotactically injected siRNA into the brains of P301S mice to reveal the suppression of tau by immunochemistry (AT180, MC1, and CP13 antibodies). We found that the Accell™ SMART pool siRNA against MAPT can effectively suppress tau expression in vitro and in vivo without a specific delivery agent. The siRNA showed a moderate distribution in the hippocampus of mice after single injection. NeuN, GFAP, Iba-1, MHC II immunoreactivities and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed neither signs of neurotoxicity or neuroinflammation nor apoptosis when MAPT siRNA is present in the hippocampus. Our data suggest that siRNA against MAPT can serve as a potential tool for gene therapy in tauopathies.

The role of hippocampal tau protein phosphorylation in isoflurane-induced cognitive dysfunction in transgenic APP695 mice.

Previous studies have shown that exposure to inhaled anesthetics can cause cognitive dysfunction, suggesting that general anesthesia might be a risk factor for the development of Alzheimer disease. However, the underlying mechanisms remain to be elucidated. In the present study, we tested our hypothesis that enhanced tau protein phosphorylation in hippocampus contributes to isoflurane-induced cognitive dysfunction in a mouse model of Alzheimer disease. Fifty-four male wild-type (WT) mice (12 months old) and 54 male amyloid precursor protein 695 (APP695) mice (12 months old) were either anesthetized for 4 hours with 1.0 minimum alveolar concentration isoflurane or sham-anesthetized (control). Learning and memory behaviors were measured using the Morris Water Maze test for mice. Phosphorylation of hippocampal tau protein at Ser262 site was analyzed with quantitative Western blotting. In the Morris Water Maze test, both WT and transgenic APP695 mice showed decreased latency times during a 4-day training period. Isoflurane exposure significantly increased the latency times on days 2 and 3 in WT mice as well as on days 3 and 4 in APP695 mice (WT: P = 0.005 for day 2 and P = 0.002 for day 3; APP695: P = 0.001 for day 3 and P < 0.0001 for day 4) and reduced platform quadrant times (WT: P < 0.0001; APP695: P < 0.0001) in both types of mice. Compared with WT mice, transgenic APP695 mice displayed worse learning and memory behaviors after isoflurane exposure (P = 0.0005 for escape latency testing on day 4 training; P = 0.009 for platform probe testing). Western blot analysis showed that the levels of phosphorylation of hippocampal tau protein at Ser262 site (tau[pS262]) in the transgenic APP695 mice were higher than those in WT mice (P < 0.0001) and that isoflurane exposure time dependently enhanced the hippocampal tau[pS262] levels in both types of mice, but this effect was much more significant in the transgenic APP695 mice (P < 0.0001). Our data also showed that isoflurane exposure had no effect on the expression of total tau protein in the hippocampi of all mice (P ≥ 0.54). Isoflurane may induce cognitive dysfunction by enhancing phosphorylation of hippocampal tau protein at Ser262 site, and this effect is more significant in transgenic APP695 mice.

Activated human microglia stimulate neuroblastoma cells to upregulate production of beta amyloid protein and tau: implications for Alzheimer's disease pathogenesis

Neuroinflammation is hypothesized to be a major driving force behind Alzheimer's disease (AD) pathogenesis. This hypothesis predicts that activated microglial cells can stimulate neurons to produce excessive amounts of β-amyloid protein (Aβ1-42) and tau. The excess Aβ1-42 forms extracellular deposits which stimulate further microglial activation. The excess tau is partially released but also becomes phosphorylated forming intracellular neurofibrillary deposits. The end result is a positive feedback mechanism which drives the disease development. To test the viability of this hypothesis, we exposed differentiated SH-SY5Y and N-tera2/D1 (N-tera2) cells to conditioned medium (CM) from LPS/IFNγ-stimulated human microglia. We found that the CM caused a large increase in the production and release of Aβ and tau. The CM also caused SH-SY5Y cells to increase their expression of amyloid precursor protein and release of its β-secretase cleaved products (sAPPβs) as well as Aβ oligomers, but the CM reduced release of its α-secretase cleaved products (sAPPαs). Direct treatment of SH-SY5Y and N-tera2 cells with the inflammatory cytokines IL-6 and IL-1β as well as with Aβ1-42, resulted in an increase in tau messenger RNA and protein expression. Pretreatment of LPS/IFNγ-stimulated human microglia cells with the nonsteroidal anti-inflammatory drugs ibuprofen and aspirin, the antioxidant GSH, the H2S donor NaSH, and the anti-inflammatory cytokine IL-10, resulted in a CM with diminished ability to stimulate tau expression. There was no effect on the morphology of SH-SY5Y cells, or on their viability, following exposure to micromolar levels of Aβ1-42. Our data indicate that reactive microglia play an important role in governing the expression of Aβ and tau, and therefore the progression of AD. They provide further evidence that appropriate anti-inflammatory treatment should be beneficial in AD.

ABNORMAL PROCESSING AND MISFOLDING OF TAU IS MODULATED BY ENDOGENOUS TAU AND MUTANT APP/PS1 BUT NOT BY ENDOGENOUS APP IN TAU TRANSGENIC MICE

analysis of brain tissue confirmed that additional treatment with OA caused behavioral and morphological hallmarks observed in human tauopathy. Data of our experiment indicate that lithium chloride can improve cognitive processes in tauopathic rats. Additionally, lithium chloride restored the pattern of intraneuronal expression of endogenous tau protein and its two phosphorylated forms, p-TauS231 and p-TauS404. Conclusions: These results indicate that presented novel animal model of human tauopathy mimics several pathologies observed in progressive dementia and is susceptible to pharmacological intervention. Therefore, it could be useful instrument to identify novel biomarkers, drug targets and therapeutic approaches for tauopathies.

Expression of cytoskeleton proteins in hypothalamic cells in winter sleeping ground squirrels Citellus pygmaeus Pallas during hibernation

We performed proteomic studies on the hypothalamus of the ground squirrel Citellus Pygmaeus Pallas during deep hibernation. We found the changes in several proteins, including the cytoskeletal protein Tau(pSer199/202), cytokeratins 8, 13, and 19, α-tubulin, and the functionally related proteins S100 and cathepsin D. Increased expression of cytokeratins, Tau(pSer199/202) protein, and cathepsin D together with decreased expression of α-tubulin in the hypothalamus of hibernating squirrels may be a feature of processes that reflect attenuation of differentiation of neurons in the brain, destruction of microtubules involved in Ca2+ transport, and increased expression of proteins that are typical of embryonic nervous tissue during deep hibernation.

Effect of taxoid and nontaxoid site microtubule-stabilizing agents on axonal transport of mitochondria in untransfected and ECFP-htau40-transfected rat cortical neurons in culture.

An important aspect of synaptic plasticity in the brain is axonal transport of essential components such as mitochondria from the soma to the synapse. For uninterrupted transport of cellular cargo down the axon, functional microtubules are required. Altered microtubule dynamics induced by changes in expression of microtubule-associated tau protein affects normal microtubule function and interferes with axonal transport. Here we investigate the effects of the nontaxoid-binding-site microtubule-stabilizing agents peloruside A (PelA) and laulimalide, compared with the taxoid-site-binding agents paclitaxel (Ptx) and ixabepilone, on axonal transport of mitochondria in 1-day-old rat pup cerebral cortical neuron cultures. The differences in effects of these two types of compound on mitochondrial trafficking were specifically compared under conditions of excess tau expression. PelA and laulimalide had no adverse effects on their own on mitochondrial transport compared with Ptx and ixabepilone, which inhibited mitochondrial run length at higher concentrations. PelA, like Ptx, was able to partially reverse the blocked mitochondrial transport seen in ECFP-htau40-overexpressing neurons, although at higher concentrations of microtubule-stabilizing agent, the PelA response was improved over the Ptx response. These results support a neuroprotective effect of microtubule stabilization in maintaining axonal transport in neurons overexpressing tau protein and may be beneficial in reducing the severity of neurodegenerative diseases such as Alzheimer's disease.

Site-specific phosphorylation of Tau protein is associated with deacetylation of microtubules in mouse spermatogenic cells during meiosis.

Tau is one of the microtubule-associated proteins and a major component of paired helical filaments, a hallmark of Alzheimer's disease. Its expression has also been indicated in the testis. However, its function and modification in the testis have not been established. Here, we analyzed the dynamics of phosphorylation patterns during spermatogenesis. The expression of Tau protein and its phosphorylation were shown in the mouse testis. Immunohistochemistry revealed that the phosphorylation was strongly detected during meiosis. Correspondingly, the expression of acetylated tubulin was inversely weakened during meiosis. These results suggest that phosphorylation of Tau protein contributes to spermatogenesis, especially in meiosis.