• The Korean Journal of Physiology and Pharmacology
• /
• 제13권3호
• /
• pp.195-200
• /
• 2009

Zinc released from excited glutamatergic neurons accelerates amyloid ${\beta}$ (A ${\beta}$) aggregation, underscoring the therapeutic potential of zinc chelation for the treatment of Alzheimer's disease (AD). Zinc can also alter A ${\beta}$ concentration by affecting its degradation. In order to elucidate the possible role of zinc influx in secretase-processed A ${\beta}$ production, SH-SY5Y cells stably expressing amyloid precursor protein (APP) were treated with pyrrolidine dithiocarbamate (PDTC), a zinc ionophore, and the resultant changes in APP processing were examined. PDTC decreased A ${\beta}$ 40 and A ${\beta}$ 42 concentrations in culture media bathing APP-expressing SH-SY5Y cells. Measuring the levels of a series of C-terminal APP fragments generated by enzymatic cutting at different APP-cleavage sites showed that both ${\beta}$-and ${\alpha}$-cleavage of APP were inhibited by zinc influx. PDTC also interfered with the maturation of APP. PDTC, however, paradoxically increased the intracellular levels of A ${\beta}$ 40. These results indicate that inhibition of secretase-mediated APP cleavage accounts -at least in part- for zinc inhibition of A ${\beta}$ secretion.

• 대한한방내과학회지
• /
• 제27권1호
• /
• pp.253-264
• /
• 2006

Object: This research investigated effects of Jujadokseo-hwan on mice with Alzheimer's Disease induced by $amyloid-{\beta}$. According to Dongyibogam, Jujadokseo-hwan can cure amnesia. Amyloid-B is believed to induce oxidative stress and inflammation in the brain, postulated to play important roles in the pathogenesis of Alzheimer's disease. In this way $Amyloid-{\beta}$ induces Alzheimer's Disease. Methods : In order to make an efficient prescription and cope with dementia, learning and memory functions of mice were tested on passive avoidance test and V-maze task. $NF-{\kappa}B$ were measured from protein derived from the brain. RT-PCR was done for !gene analysis. Primers were protein kinase Band $NGF-{\alpha}$. Results : 1. Jujadokseo-hwan was effective for memory capacity on passive avoidance test. but noneffective for spatial memory capacity and locomotor activity on Y -maze task. 2. The measurement of $NF-{\kappa}B$ showed upward tendancies and the result of RT-PCR showed up-regulation when given Jujadokseo-hwan by mouth. Conclusion: Results suggest that Jujadokseo-hwan is effective on mice with Alzheimer's Disease induced by $amyloid-{\beta}$.

• Biomolecules & Therapeutics
• /
• 제20권3호
• /
• pp.245-255
• /
• 2012

Amyloid-${\beta}$ peptide ($A{\beta}$) is still best known as a molecule to cause Alzheimer's disease (AD) through accumulation and deposition within the frontal cortex and hippocampus in the brain. Thus, strategies on developing AD drugs have been focused on the reduction of $A{\beta}$ in the brain. Since accumulation of $A{\beta}$ depends on the rate of its synthesis and clearance, the metabolic pathway of $A{\beta}$ in the brain and the whole body should be carefully explored for AD research. Although the synthetic pathway of $A{\beta}$ is equally important, we summarize primarily the clearance pathway in this paper because the former has been extensively reviewed in previous studies. The clearance of $A{\beta}$ from the brain is accomplished by several mechanisms which include non-enzymatic and enzymatic pathways. Nonenzymatic pathway includes interstitial fluid drainage, uptake by microglial phagocytosis, and transport across the blood vessel walls into the circulation. Multiple $A{\beta}$-degrading enzymes (ADE) implicated in the clearance process have been identified, which include neprilysin, insulin-degrading enzyme, matrix metalloproteinase-9, glutamate carboxypeptidase II and others. A series of studies on $A{\beta}$ clearance mechanism provide new insight into the pathogenesis of AD at the molecular level and suggest a new target for the development of novel therapeutics.

• Bulletin of the Korean Chemical Society
• /
• 제33권11호
• /
• pp.3671-3675
• /
• 2012

${\beta}$-Amyloid accumulation in the brain is a pathological hallmark of Alzheimer's disease (AD). Since early detection of ${\beta}$-amyloid may facilitate more successful and timely therapeutic interventions, many investigators have focused on developing AD diagnostic reagents that can penetrate the blood-brain barrier (BBB). Oleanolic acid (OA) is a substance found in a variety of plants that has been reported to prevent the progression of AD in mice. In this study, we synthesized and evaluated a new radioligand in which OA was conjugated to lactoferrin (Lf, an iron-binding glycoprotein that crosses the BBB) for the diagnosis of AD. In an in vitro study in which OA-Lf was incubated with ${\beta}$-amyloid (1-42) aggregates for 24 h, we found that OA-Lf effectively inhibited ${\beta}$-amyloid aggregation and fibril formation. In vivo studies demonstrated that $^{123}I$-OA-Lf brain uptake was higher than$^{123}I$-Lf uptake. Therefore, radiolabeled OA-Lf may have diagnostic potential for ${\beta}$-amyloid imaging.

• 대한의생명과학회지
• /
• 제25권1호
• /
• pp.7-14
• /
• 2019

Alzheimer's disease (AD) is highly prevalent in dementia, with no specifically effective treatment having yet been discovered. Amyloid plaques are one of the key hallmarks of AD. Transgenic mouse models exhibiting Alzheimer's disease-like pathology have been widely used to study the pathophysiology of Alzheimer's disease. In this study, we showed an age-dependent correlation between cognitive function, pathological findings, and [F-18] Florbetaben (FBB) PET images. Nineteen transgenic mice (12 with AD, 7 with controls) were used for this study. We observed an increase in ${\beta}$-Amyloid deposition ($A{\beta}$) in brain tissue and [F-18] FBB amyloid PET imaging in the AD group. The [F-18] FBB data showed a mildly negative trend with cognitive function. Pathological findings were negatively correlated with cognitive functions. These finding suggests that amyloid beta deposition can be well-monitored with [F-18] FBB PET and a decline in cognitive function is related to the increase in amyloid plaque burden.

• Journal of Yeungnam Medical Science
• /
• 제35권1호
• /
• pp.1-6
• /
• 2018

Alzheimer's disease (AD) is a neurodegenerative disorder associated with extracellular plaques, composed of amyloid-beta ($A{\beta}$), in the brain. Although the precise mechanism underlying the neurotoxicity of $A{\beta}$ has not been established, $A{\beta}$ accumulation is the primary event in a cascade of events that lead to neurofibrillary degeneration and dementia. In particular, the $A{\beta}$ burden, as assessed by neuroimaging, has proved to be an excellent predictive biomarker. Positron emission tomography, using ligands such as $^{11}C$-labeled Pittsburgh Compound B or $^{18}F$-labeled tracers, such as $^{18}F$-florbetaben, $^{18}F$-florbetapir, and $^{18}F$-flutemetamol, which bind to $A{\beta}$ deposits in the brain, has been a valuable technique for visualizing and quantifying the deposition of $A{\beta}$ throughout the brain in living subjects. $A{\beta}$ imaging has very high sensitivity for detecting AD pathology. In addition, it can predict the progression from mild cognitive impairment to AD, and contribute to the development of disease-specific therapies.

• 동의생리병리학회지
• /
• 제24권1호
• /
• pp.91-95
• /
• 2010

Alzheimer's disease (AD) is characterized pathologically by the presence of intracellular neurofibrillary tangles and deposition of ${\beta}$-amyloid (A${\beta}$) peptides. It is urgent to develop effective therapies for the treatment of AD, since our society rapidly accelerate aging. A${\beta}$ peptides have been believed to be neurotoxic and now are also considered to have affects on the mechanism of memory formation, which are generated by processing of amyloid precursor protein (APP). In this study, effects of Styrax Liquides (SL) on the metabolism of APP were analyzed. SL inhibited the secretion of A${\beta}$ from the Neuro2a cell line (APPswe cell) expressing a mutation of APPswe. Immunoblotting study showed that it inhibited ${\beta}$-site APP cleaving enzyme (BACE) from the APPswe cells. We suggest that SL inhibits APP metabolism and A${\beta}$ generation by the means of BACE inhibitory mechanism. This is the first report that SL inhibits the secretion of A${\beta}$ peptides from neuroblastoma cells.

• Bulletin of the Korean Chemical Society
• /
• 제29권8호
• /
• pp.1505-1509
• /
• 2008

Comparative molecular simulations were performed to establish molecular interaction and inhibitory effect of flavonoid myricetin on formation of amyloid fibris. For computational comparison, the conformational stability of myricetin with amyloid $\beta$ -peptide (A$\beta$ ) and $\beta$ -amyloid fibrils (fA$\beta$) were traced with multiple molecular dynamics simulations (MD) using the CHARMM program from Monte Carlo docked structures. Simulations showed that the inhibition by myricetin involves binding of the flavonoid to fA$\beta$ rather than A$\beta$ . Even in MD simulations over 5 ns at 300 K, myricetin/fA$\beta$ complex remained stable in compact conformation for multiple trajectories. In contrast, myricetin/A$\beta$ complex mostly turned into the dissociated conformation during the MD simulations at 300 K. These multiple MD simulations provide a theoretical basis for the higher inhibitory effect of myricetin on fibrillogenesis of fA$\beta$ relative to A$\beta$ . Significant binding between myricetin and fA$\beta$ observed from the computational simulations clearly reflects the previous experimental results in which only fA$\beta$ had bound to the myricetin molecules.

• 한국독성학회:학술대회논문집
• /
• 한국독성학회 2003년도 춘계학술대회 논문집
• /
• pp.93-94
• /
• 2003

beta-Amyloid peptide is considered to be responsible for the formation of senile plagues that accumulate in the brains of patients with Alzheimers disease. There has been a paucity of evidence to support the involvement of reactive oxygen and/or nitrogen species (ROS and/or RNS) in beta-amyloid-induced neuronal cell death. (omitted)

• BMB Reports
• /
• 제43권6호
• /
• pp.413-418
• /
• 2010

Beta-Amyloid ($A{\beta}$)-induced neuroinflammation is one of the key events in the development of neurodegenerative disease. We previously reported that KHG21834, a benzothiazole derivative, attenuates $A{\beta}$-induced degeneration of cortical and mesencephalic neurons in vitro. In the present work, we show that KHG21834 reduces $A{\beta}$-mediated neuroinflammation in brain. In vivo intracerebroventricular infusion of KHG21834 leads to decreases in the numbers of activated astrocytes and microglia and level of proinflammatory cytokines such as interleukin-$1{\beta}$ and tumor necrosis factor-$\alpha$ induced by $A{\beta}$ in the hippocampus. This suppression of neuroinflammation is associated with decreased neuron loss, restoration of synaptic dysfunction biomarkers in the hippocampus to control level, and diminished amyloid deposition. These results may suggest the potential therapeutic efficacy of KHG21834 for the treatment of $A{\beta}$-mediated neuroinflammation.