• Proceeding of EDISON Challenge
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• 2014.03a
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• pp.237-249
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• 2014

Deposition of amyloid-${\beta}$ ($A{\beta}$) proteins is the conventional pathological hallmark of Alzheimer's disease (AD). The $A{\beta}$ protein formed from the amyloid precursor protein is predominated by the 40 residue protein ($A{\beta}40$) and by the 42 residue protein ($A{\beta}42$). While $A{\beta}40$ and $A{\beta}42$ differ in only two amino acid residues at the C-terminal end, $A{\beta}42$ is much more prone to aggregate and exhibits more neurotoxicity than $A{\beta}40$. Here, we investigate the molecular origin of the difference in the aggregation propensity of these two proteins by performing fully atomistic, explicit-water molecular dynamics simulations. Then, it is followed by the solvation thermodynamic analysis based on the integral-equation theory of liquids. We find that $A{\beta}42$ displays higher tendency to adopt ${\beta}$-sheet conformations than $A{\beta}40$, which would consequently facilitate the conversion to the ${\beta}$-sheet rich fibril structure. Furthermore, the solvation thermodynamic analysis on the simulated protein conformations indicates that $A{\beta}42$ is more hydrophobic than $A{\beta}40$, implying that the surrounding water imparts a larger thermodynamic driving force for the self-assembly of $A{\beta}42$. Taken together, our results provide structural and thermodynamic grounds on why $A{\beta}42$ is more aggregation-prone than $A{\beta}40$ in aqueous environments.

• BMB Reports
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• v.43 no.10
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• pp.649-655
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• 2010

Alzheimer's disease (AD) is the most common age-dependent neurodegenerative disorder and shows progressive memory loss and cognitive decline. Intraneuronal filaments composed of aggregated hyperphosphorylated tau protein, called neurofibrillary tangles, along with extracellular accumulations of amyloid $\beta$ protein (A$\beta$), called senile plaques, are known to be the neuropathological hallmarks of AD. In light of recent studies, epigenetic modification has emerged as one of the pathogenic mechanisms of AD. Epigenetic changes encompass an array of molecular modifications to both DNA and chromatin, including transcription factors and cofactors. In this review, we summarize how DNA methylation and changes to DNA chromatin packaging by post-translational histone modification are involved in AD. In addition, we describe the role of SIRTs, histone deacetylases, and the effect of SIRT-modulating drugs on AD. Lastly, we discuss how amyloid precursor protein (APP) intracellular domain (AICD) regulates neuronal transcription. Our understanding of the epigenomes and transcriptomes of AD may warrant future identification of novel biological markers and beneficial therapeutic targets for AD.

• Journal of Physiology & Pathology in Korean Medicine
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• v.19 no.1
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• pp.242-245
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• 2005

The most common feature of neurodegenerative disease (i.e. Alzheimer's disease, AD) is the increased number of activated microglial cells nearby the pathogenic area of the brain, such as amyloid plaque in AD. An abnormality of protein regulation and an imbalance of clearance against ${\beta}-amyloid\;(A{\beta})$ produced amyloid precursor protein (APP) can turn microglia into the activated feature out of the ramified resting phase. We examined the possibility that ginsenoside Rb1 could attenuate the microglial activation induced by massive $A{\beta}$ that has known to induce a chronic inflammation, which is a major cause of AD by damaging neuronal cells (i.e. apoptosis or necrosis). Aggregated $A{\beta}42\;(5\;{\mu}M)$ peptide was used with lipopolysaccharide (LPS) ($10\;{\mu}g$) for a comparative control up to 48hours. We found that Rb1 reduced the production of nitric oxide as well as proinflammatory cytokines, such as $IL-1{\beta}$ and $TNF-{\alpha}$.

• Development and Reproduction
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• v.21 no.4
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• pp.417-424
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• 2017

Alzheimer's disease (AD) is neurodegenerative disease, characterized by the progressive decline of memory, cognitive functions, and changes in personality. The major pathological features in postmortem brains are neurofibrillary tangles and amyloid beta ($A{\beta}$) deposits. The majority of AD cases are sporadic and age-related. Although AD pathogenesis has not been established, aging and declining mitochondrial function has been associated. Mitochondrial dysfunction has been observed in AD patients' brains and AD mice models, and the mice with a genetic defect in mitochondrial complex I showed enhanced $A{\beta}$ level in vivo. To elucidate the role of mitochondrial complex I in AD, we used SH-SY5Y cells transfected with DNA constructs expressing human amyloid precursor protein (APP) or human Swedish APP mutant (APP-swe). The expression of APP-swe increased the level of $A{\beta}$ protein in comparison with control. When complex I was inhibited by rotenone, the increase of ROS level was remarkably higher in the cells overexpressing APP-swe compared to control. The number of dead cell was significantly increased in APP-swe-expressing cells by complex I inhibition. We suggest that complex I dysfunction accelerate amyloid toxicity and mitochondrial complex I dysfunction in aging may contribute to the pathogenesis of sporadic AD.

• Korean Journal of Biological Psychiatry
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• v.5 no.1
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• pp.66-70
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• 1998

Apoptosis is a form of cell death in which the cells shrink and exhibit nuclear chromatin condensation and DNA fragmentation, and yet maintain membrane integrity. Many lines of evidence have shown that brain neurons are vulnerable to degeneration by apoptosis. Also it has been suggested that apoptosis is one of the mechanism contributing neuronal loss in Alzheimer's disease(AD), since the conditions in the disease($A{\beta}$ peptide, oxidative stress, low energy metabolism) are the inducers that activate apoptosis. Indeed some neurons in vulnerable regions of the AD brain show DNA damage, chromatin condensation, and apoptic bodies. Consistently, mutations in AD causative genes(Amyloid precursor protein, Presenilin-1 and Presenilin- 2) increase $A{\beta}$ $peptide_{1-42}(A{\beta}_{1-42})$ and sensitize neuronal cell to apoposis. However, several lines of evidence have shown that the location of neuronal loss and $A{\beta}$ peptide deposition is not correlated in AD brain and transgenic mice brain over-expressing $A{\beta}_{1-42}$. Taken together, these data may indicated that $A{\beta}$ peptide(and other causative factors of AD) can interact with other cellular insults or risk factors to exacerbate pathological mechansim of AD through apoptosis. Thus, this review discusses possible role and mechanism of apoptosis in AD.

• BMB Reports
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• v.43 no.10
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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.

• Korean Journal of Biological Psychiatry
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• v.6 no.2
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• pp.149-152
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• 1999

Transgenic mice models of Alzheimer's disease were produced by overexpressing APP(amyloid precursor protein) mutant and presenilin mutant genes using the promotors that induced neuronal expression. The neuropathologies, electrophysiological changes and behavioral changes that were demonstrated in these transgenic mice models were amyloid changes, gliotic changes, A-beta increases, deficit in LTP(long-term potentiation) and behavioral changes. Some or all of the above changes were found in each transgenic mice model. These models generally showed amyloid neuropathology but they usually lacked the neurofibrillary tangles. So, they can be regarded as partial models of Alzheimer's disease. The development of them is undoubtedly the great progress toward future research.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.136.1-136.1
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• 2003

$\beta$-amyloid (A$\beta$) peptide produced from amyloid precursor protein (APP) is a major cause of Alzheimer's disease (AD). Therefore, in early phase of AD, imbalance of the production and the clearance of $A\beta$ is regarded as an important factor to progressive AD presenting senile plaque, a hallmark of AD. In the present study, we wanted to verify whether Rg3 can playa role in helping microglia engulfing $A\beta$ peptides. Validations for the study was conducted by using DiI-Ac-LDL, which attached only on type A macrophage scavenger receptor (MSR-A) and ligands for he receptor, fucoidan. (omitted)

• BMB Reports
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• v.52 no.7
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• pp.439-444
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• 2019

Although hypoxic/ischemic injury is thought to contribute to the incidence of Alzheimer's disease (AD), the molecular mechanism that determines the relationship between hypoxia-induced ${\beta}$-amyloid ($A{\beta}$) generation and development of AD is not yet known. We have now investigated the protective effects of N,4,5-trimethylthiazol-2-amine hydrochloride (KHG26702), a novel thiazole derivative, on oxygen-glucose deprivation (OGD)-reoxygenation (OGD-R)-induced $A{\beta}$ production in SH-SY5Y human neuroblastoma cells. Pretreatment of these cells with KHG26702 significantly attenuated OGD-R-induced production of reactive oxygen species and elevation of levels of malondialdehyde, prostaglandin $E_2$, interleukin 6 and glutathione, as well as superoxide dismutase activity. KHG26702 also reduced OGD-R-induced expression of the apoptotic protein caspase-3, the apoptosis regulator Bcl-2, and the autophagy protein becn-1. Finally, KHG26702 reduced OGD-R-induced $A{\beta}$ production and cleavage of amyloid precursor protein, by inhibiting secretase activity and suppressing the autophagic pathway. Although supporting data from in vivo studies are required, our results indicate that KHG26702 may prevent neuronal cell damage from OGD-R-induced toxicity.

• Journal of Plant Biotechnology
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• v.47 no.4
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• pp.283-288
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• 2020

Although the evolution of Arabidopsis thaliana and humans diverged approximately 1.6 billion years ago, recent studies have demonstrated that protein function and cellular processes involved in disease response remain remarkably conserved. Particularly, γ-secretase, a multisubunit protein complex that participates in intramembrane proteolysis (RIP) regulation, is also known to mediate the cleavage of more than 80 substrates including the amyloid precursor protein (APP) and the Notch receptor. Although the genes (PS1/2, APH-1, PEN-2, and NCT) coding for the γ-secretase complex components are present in plant genomes, their function remains largely uncharacterized. Given that the deposition of 42 amino acid long amyloid-β peptides (hAβ₄₂) is thought to be one of the main causes of Alzheimer's disease, we aimed to examine the physiological effects of hAβ₄₂ peptides on plants. Interestingly, we found that Arabidopsis protoplast death increased after 24 h of exposure to 3 or 5 µM hAβ₄₂ peptides. Furthermore, transgenic Arabidopsis plants overexpressing the hAβ₄₂ gene exhibited changes in primary root length and silique phyllotaxy. Taken together, our results demonstrate that hAβ₄₂ peptides, a metazoan protein, significantly affect Arabidopsis protoplast viability and plant morphology.