• 생물정신의학
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• 제8권1호
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• pp.62-70
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• 2001

Alzheimer's disease(AD) is associated with a characteristic neuropathology. The major hallmarks of AD are senile plaques (SPs) and neurofibrillary tangles(NFTs). ${\beta}$-amyloid protein($A{\beta}$) is derived from the proteolysis of amyloid precursor protein(APP) and then converted to SPs. Mature SPs produce cytotoxicity through direct toxic effects and activation of microglia and complement. NFTs are composed of paired helical filaments(PHFs) including abnormally phosphorylated form of the microtubule-associated protein(MAP) tau and increased tau level in cerebrospinal fluid may be observed in most AD. The aggregation of $A{\beta}$ and tau formation are thought to be a final common pathway of AD. Acetylcholine, dopamine, serotonin, GABA and their receptors are associated with AD. Especially, decreased nicotinic acetylcholine receptors(nAChRs) in AD are reported. Genetic lesions associated with AD are mutations in the structural genes for the APP located on chromosome 21, presenilin(PSN)1 located on chromosome 14 and PSN2 located on chromosome 1. Also, trisomy 21, Apo-E gene located on chromosome 19, PMF locus, low density lipoprotein receptor-related protein and ${\alpha}$-macroglobulin increase risk of AD. In this article, we will review about the neurobiology of AD and some newly developed research areas.

• BMB Reports
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• 제49권8호
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• pp.405-413
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• 2016

Tau proteins, which stabilize the structure and regulate the dynamics of microtubules, also play important roles in axonal transport and signal transduction. Tau proteins are missorted, aggregated, and found as tau inclusions under many pathological conditions associated with neurodegenerative disorders, which are collectively known as tauopathies. In the adult human brain, tau protein can be expressed in six isoforms due to alternative splicing. The aberrant splicing of tau pre-mRNA has been consistently identified in a variety of tauopathies but is not restricted to these types of disorders as it is also present in patients with non-tau proteinopathies and RNAopathies. Tau mis-splicing results in isoform-specific impairments in normal physiological function and enhanced recruitment of excessive tau isoforms into the pathological process. A variety of factors are involved in the complex set of mechanisms underlying tau mis-splicing, but variation in the cis-element, methylation of the MAPT gene, genetic polymorphisms, the quantity and activity of spliceosomal proteins, and the patency of other RNA-binding proteins, are related to aberrant splicing. Currently, there is a lack of appropriate therapeutic strategies aimed at correcting the tau mis-splicing process in patients with neurodegenerative disorders. Thus, a more comprehensive understanding of the relationship between tau mis-splicing and neurodegenerative disorders will aid in the development of efficient therapeutic strategies for patients with a tauopathy or other, related neurodegenerative disorders.

• BMB Reports
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• 제43권10호
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• pp.704-709
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• 2010

The Swedish mutation (K595N/M596L) of amyloid precursor protein (APP-swe) has been known to increase abnormal cleavage of cellular APP by Beta-secretase (BACE), which causes tau protein hyperphosphorylation and early-onset Alzheimer's disease (AD). Here, we analyzed the effect of APP-swe in global gene expression using deep transcriptome sequencing technique. We found 283 genes were down-regulated and 348 genes were up-regulated in APP-swe expressing H4-swe cells compared to H4 wild-type cells from a total of approximately 74 million reads of 38 base pairs from each transcriptome. Two independent mechanisms such as kinase and phosphatase signaling cascades leading hyperphosphorylation of tau protein were regulated by the expression of APP-swe. Expressions of catalytic subunit as well as several regulatory subunits of protein phosphatases 2A were decreased. In contrast, expressions of tau-phosphorylating glycogen synthase kinase $3\beta$(GSK-3$\beta$), cyclin dependent kinase 5 (CDK5), and cAMP-dependent protein kinase A (PKA) catalytic subunit were increased. Moreover, the expression of AD-related Aquaporin 1 and presenilin 2 expression was regulated by APP-swe. Taken together, we propose that the expression of APP-swe modulates global gene expression directed to AD pathogenesis.

• Fisheries and Aquatic Sciences
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• 제17권2호
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• pp.255-261
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• 2014

An 8-week feeding trial was conducted to investigate the effects of dietary taurine supplementation on the growth performance of juvenile rock bream, Oplegnathus fasciatus. Triplicate groups of 25 fish averaging $2.72{\pm}0.04$ g ($mean{\pm}SD$) were fed one of six experimental diets prepared by adding taurine at 0%, 0.25%, 0.5%, 1.0%, 1.5% and 3.0% (Control, $Tau_{0.25}$, $Tau_{0.5}$, $Tau_{1.0}$, $Tau_{1.5}$ and $Tau_{3.0}$, respectively). At the end of the feeding trial, the weight gain, specific growth rate and protein efficiency ratio of fish fed the $Tau_{0.5}$, $Tau_{1.0}$ and $Tau_{1.5}$ diets were significantly higher (P < 0.05) than those of fish fed the Control and $Tau_{0.25}$ diets. The feed efficiency of fish fed the $Tau_{0.5}$ diet was significantly higher than that of fish fed the Control, $Tau_{0.25}$ and $Tau_{3.0}$ diets. Fish fed the $Tau_{1.0}$ diet had higher whole-body crude protein content than fish fed the Control diet, while the crude lipid content of fish fed the $Tau_{1.5}$ and $Tau_{3.0}$ diets was significantly lower than that of fish fed the Control and $Tau_{0.25}$ diets. An ANOVA suggested that the optimum level of dietary taurine supplementation to improve growth and reduce the body lipid contents of juvenile rock bream, O. fasciatus, was 0.5%, while a broken line analysis of weight gain indicated a level of 0.62%.

• BMB Reports
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• 제42권8호
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• pp.467-474
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• 2009

The modification of proteins by reversible phosphorylation is a key mechanism in the regulation of various physiological functions. Abnormal protein kinase or phosphatase activity can cause disease by altering the phosphorylation of critical proteins in normal cellular and disease processes. Alzheimer' disease (AD), typically occurring in the elderly, is an irreversible, progressive brain disorder characterized by memory loss and cognitive decline. Accumulating evidence suggests that protein kinase and phosphatase activity are altered in the brain tissue of AD patients. Tau is a highly recognized phosphoprotein that undergoes hyperphosphorylation to form neurofibrillary tangles, a neuropathlogical hallmark with amyloid plaques in AD brains. This study is a brief overview of the altered protein phosphorylation pathways found in AD. Understanding the molecular mechanisms by which the activities of protein kinases and phosphatases are altered as well as the phosphorylation events in AD can potentially reveal novel insights into the role aberrant phosphorylation plays in the pathogenesis of AD, providing support for protein phosphorylation as a potential treatment strategy for AD.

• Bulletin of the Korean Chemical Society
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• 제31권12호
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• pp.3838-3841
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• 2010

• Natural Product Sciences
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• 제26권3호
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• pp.221-229
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• 2020

This study was undertaken to investigate the protective effect of rice bran oil (RBO) on amyloid β protein (Aβ) (25-35)-induced memory impairment and brain damage in an ICR mouse model. Memory impairment was produced by intracerebroventricular microinjection of 15 nmol Aβ (25-35) and assessed using the passive avoidance test. Treatment with RBO at 0.1, 0.5, or 1 mL/kg (p.o. daily for 8 days) protected against Aβ (25-35)-induced memory impairment. Furthermore, Aβ (25-35)-induced decreases in glutathione and increases in lipid peroxidation and cholinesterase activity in brain tissue were inhibited by RBO, and Aβ (25-35)-induced increases of phosphorylated mitogen-activated protein kinases (MAPKs) and inflammatory factors, and changes in the levels of apoptosis-related proteins were significantly inhibited by RBO. Furthermore, Aβ (25-35) suppressed the PI3K/Akt pathway and the phosphorylation of CREB, but increased phosphorylation of tau (p-tau) in mice brain; these effects were significantly inhibited by administration of RBO. These results suggest that RBO inhibits Aβ (25-35)-induced memory impairment by inducing anti-apoptotic and anti-inflammatory effects, promoting PI3K/Akt/CREB signaling, and thus, inhibiting p-tau formation.

• Asian Pacific Journal of Cancer Prevention
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• 제17권4호
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• pp.1967-1971
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• 2016

Background: In tumor cells, aberrant differentiation programs have been described. Several neuronal proteins have been found associated with morphological neuronal-glial changes in breast cancer (BCa). These neuronal proteins have been related to mechanisms that are involved in carcinogenesis; however, this regulation is not well understood. Microtubule-associated protein-tau (MAP-Tau) has been describing in BCa but not its variants. This finding could partly explain the neuronal-glial morphology of BCa cells. Our aim was to determine mRNA expression of MAP-tau variants 2, 4 and 6 in breast cancer cell lines. Materials and Methods: Cultured cell lines MCF-10A, MDA-MB-231, SKBR3 and T47D were observed under phase-contrast microscopy for neural morphology and analyzed for gene expression of MAP-Tau transcript variants 2, 4 and 6 by real-time PCR. Results: Regarding morphology like neural/glial cells, T47D line shown more cells with these features than MDA-MB-231 and SKBR. In another hand, we found much greater mRNA expression of MAP-Tau transcript variants 2, and to a lesser extent 4 and 6, in T47D cells than the other lines. In conclusion, regulation of MAP-Tau could bring about changes in cytoskeleton, cell morphology and motility; these findings cast further light on neuronal transdifferentiation in BCa.

• Biomolecules & Therapeutics
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• 제31권1호
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• pp.127-138
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• 2023

Glycogen synthase kinase-3β (GSK-3β) is an important serine/threonine kinase that implicates in multiple cellular processes and links with the neurodegenerative diseases including Alzheimer's disease (AD). In this study, structure-based virtual screening was performed to search database for compounds targeting GSK-3β from Enamine's screening collection. Of the top-ranked compounds, 7 primary hits underwent a luminescent kinase assay and a cell assay using human neuroblastoma SH-SY5Y cells expressing Tau repeat domain (Tau_RD) with pro-aggregant mutation ΔK280. In the kinase assay for these 7 compounds, residual GSK-3β activities ranged from 36.1% to 90.0% were detected at the IC₅₀ of SB-216763. In the cell assay, only compounds VB-030 and VB-037 reduced Tau aggregation in SH-SY5Y cells expressing ΔK280 Tau_RD-DsRed folding reporter. In SH-SY5Y cells expressing ΔK280 Tau_RD, neither VB-030 nor VB-037 increased expression of GSK-3α Ser21 or GSK-3β Ser9. Among extracellular signal-regulated kinase (ERK), AKT serine/threonine kinase 1 (AKT), mitogen-activated protein kinase 14 (P38) and mitogenactivated protein kinase 8 (JNK) which modulate Tau phosphorylation, VB-037 attenuated active phosphorylation of P38 Thr180/ Tyr182, whereas VB-030 had no effect on the phosphorylation status of ERK, AKT, P38 or JNK. However, both VB-030 and VB-037 reduced endogenous Tau phosphorylation at Ser202, Thr231, Ser396 and Ser404 in neuronally differentiated SH-SY5Y expressing ΔK280 Tau_RD. In addition, VB-030 and VB-037 further improved neuronal survival and/or neurite length and branch in mouse hippocampal primary culture under Tau cytotoxicity. Overall, through inhibiting GSK-3β kinase activity and/or p-P38 (Thr180/Tyr182), both compounds may serve as promising candidates to reduce Tau aggregation/cytotoxicity for AD treatment.

• 운동영양학회지
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• 제16권2호
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• pp.93-100
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• 2012

Alzheimer's disease (AD) is the most common cause of dementia in adults. Microtubule associated protein tau is abnormally phosphorylated in AD and aggregates as paired helical filaments (PHFs) in neurofibrillary tangles (NFTs). NFTs are the most common intraneuronal inclusion in the brains of patients with AD and have been implicated in mediating neuronal cell death and cognitive deficit. Aberrant phosphorylation of tau is an early pathological event in AD, but the underlying mechanisms are unclear. MAP kinases are a family of Serine/Threonine (Ser/Thr) kinases that involved hyper - phosphorylation of tau in AD. The purpose of this study was to investigate the effect of treadmill exercise on phosphorylation of tau level and activation of MAPKs including JNK, ERK, p38-MAPK. To address this, Tg mouse model of AD, Tg-NSE/hTau 23, which expresses human tau 23 in the brain, was chosen. Animals were subjected to treadmill exercise for 12 weeks from 24 months of age. Treadmill exercise in Tg group improved cognitive function compared with Tg-SED group in watermaze test. In addition, treadmill exercised Tg mice significantly reduced the activation of JNK54/46, p38-MAPK and tau (Ser404, Ser202, Thr231), and increased activation of ERK44/42 in cerebral cortex. These results suggest that treadmill exercise may provide a therapeutic potential to alleviate the tau pathology like AD.