Convergence Research Center for Diagnosis Treatment and Care System of Dementia

As nano- and micro-sized plastics accumulate in the environment and the food chain of animals, including humans, it is imperative to assess the effects of nanoplastics in living organisms in a systematic manner, especially because of their ability to adsorb potential toxicants such as pollutants, heavy metals, and organic macromolecules that coexist in the environment. Using the zebrafish embryo as an animal model, we investigated the bioaccumulation and in vivo toxicity of polystyrene (PS) nanoplastics individually or in combination with the Au ion. We showed that smaller PS nanoplastics readily penetrated the chorion and developing embryos and accumulated throughout the whole body, mostly in lipid-rich regions such as in yolk lipids. We also showed that PS nanoplastics induced only marginal effects on the survival, hatching rate, developmental abnormalities, and cell death of zebrafish embryos but that these effects were synergistically exacerbated by the Au ion in a dose- and size-dependent manner. Such exacerbation of toxicity was well correlated with the production of reactive oxygen species and the pro-inflammatory responses synergized by the presence of PS, supporting the combined toxicity of PS and Au ions. The synergistic effect of PS on toxicity appeared to relate to mitochondrial damage as determined by ultrastructural analysis. Taken together, the effects of PS nanoplastics were marginal but could be a trigger for exacerbating the toxicity induced by other toxicants such as metal ions.

Brain diseases and disorders such as Alzheimer disease, Parkinson disease, depression, schizophrenia, autism, and addiction lead to reduced quality of daily life through abnormal thoughts, perceptions, emotional states, and behavior. While the underlying mechanisms remain poorly understood, human and animal studies have supported a role of neuroinflammation in the etiology of these diseases. In the central nervous system, an increased inflammatory response is capable of activating microglial cells, leading to the release of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. In turn, the pro-inflammatory cytokines aggravate and propagate neuroinflammation, degenerating healthy neurons and impairing brain functions. Therefore, activated microglia may play a key role in neuroinflammatory processes contributing to the pathogenesis of psychiatric disorders and neurodegeneration.

= 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Long-term treatment with KDS2010 does not induce compensatory mechanisms, thereby significantly attenuating increased astrocytic GABA levels and astrogliosis, enhancing synaptic transmission, and rescuing learning and memory impairments in APP/PS1 mice.

Amyloid and tau aggregation are implicated in manifold neurodegenerative diseases and serve as two signature pathological hallmarks in Alzheimer's disease (AD). Though aging is considered as a prominent risk factor for AD pathogenesis, substantial evidence suggests that an imbalance of essential biometal ions in the body and exposure to certain metal ions in the environment can potentially induce alterations to AD pathology. Despite their physiological importance in various intracellular processes, biometal ions, when present in excessive or deficient amounts, can serve as a mediating factor for neurotoxicity. Recent studies have also demonstrated the contribution of metal ions found in the environment on mediating AD pathogenesis. In this regard, the neuropathological features associated with biometal ion dyshomeostasis and environmental metal ion exposure have prompted widespread interest by multiple research groups. In this review, we discuss and elaborate on findings from previous studies detailing the possible role of both endogenous and exogenous metal ions specifically on amyloid and tau pathology in AD.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive symptoms of learning and memory deficits. Such cognitive impairments are attributed to brain atrophy resulting from progressive neuronal and synaptic loss; therefore, alleviation of neural cell death is as an important target of treatment as other classical hallmarks of AD, such as aggregation of amyloid-β (Aβ) and hyperphosphorylation of tau. Here, we found that an anti-necroptotic molecule necrostatin-1 (Nec-1) directly targets Aβ and tau proteins, alleviates brain cell death and ameliorates cognitive impairment in AD models. In the cortex and hippocampus of APP/PS1 double-transgenic mice, Nec-1 treatment reduced the levels of Aβ oligomers, plaques and hyperphosphorylated tau without affecting production of Aβ, while it altered the levels of apoptotic marker proteins. Our results showing multiple beneficial modes of action of Nec-1 against AD provide evidence that Nec-1 may serve an important role in the development of preventive approach for AD.

Alzheimer's disease (AD) is a progressive, neurodegenerative brain disorder that attacks neurotransmitters, brain cells, and nerves, affecting brain functions, memory, and behaviors and then finally causing dementia on elderly people. Despite its significance, there is currently no cure for it. However, there are medicines available on prescription that can help delay the progress of the condition. Thus, early diagnosis of AD is essential for patient care and relevant researches. Major challenges in proper diagnosis of AD using existing classification schemes are the availability of a smaller number of training samples and the larger number of possible feature representations. In this paper, we present and compare AD diagnosis approaches using structural magnetic resonance (sMR) images to discriminate AD, mild cognitive impairment (MCI), and healthy control (HC) subjects using a support vector machine (SVM), an import vector machine (IVM), and a regularized extreme learning machine (RELM). The greedy score-based feature selection technique is employed to select important feature vectors. In addition, a kernel-based discriminative approach is adopted to deal with complex data distributions. We compare the performance of these classifiers for volumetric sMR image data from Alzheimer's disease neuroimaging initiative (ADNI) datasets. Experiments on the ADNI datasets showed that RELM with the feature selection approach can significantly improve classification accuracy of AD from MCI and HC subjects.

Background: DYRK1A maps to the Down syndrome critical region at 21q22. Mutations in this kinase-encoding gene have been reported to cause microcephaly associated with either intellectual disability or autism in humans. Intellectual disability accompanied by microcephaly was recapitulated in a murine model by overexpressing Dyrk1a which mimicked Down syndrome phenotypes. However, given embryonic lethality in homozygous knockout (KO) mice, no murine model studies could present sufficient evidence to link Dyrk1a dysfunction with autism. To understand the molecular mechanisms underlying microcephaly and autism spectrum disorders (ASD), we established an in vivo dyrk1aa KO model using zebrafish.

In a mass casualty incident, the factors that determine the survival rate of injured patients are diverse, but one of the key factors is the time for triage. Additionally, the main factor that determines the time of triage is the number of medical personnel. However, when relying on a small number of medical personnel, the ability to increase survivability is limited. Therefore, developing a classification model for survival prediction that can quickly and precisely triage via wearable devices without medical personnel is important. In this study, we designed a consciousness index to substitute the factor by manpower and improved the classification accuracy by applying a machine learning algorithm. First, logistic regression analysis using vital signs and a consciousness index capable of remote monitoring through wearable devices confirmed the high efficiency of the consciousness index. We then developed a classification model with high accuracy which corresponds to existing injury severity scoring systems through the machine learning algorithms. We extracted 460,865 cases which met our criteria for developing the survival prediction from the national sample project in the national trauma databank which contains 408,316 cases of blunt injury and 52,549 cases of penetrating injury. Among the dataset, 17,918 (3.9%) cases died while the other survived. The AUCs with 95% confidence intervals (CIs) for the different models with the proposed simplified consciousness score as follows: RTS (as baseline), 0.78 (95% CI = 0.775 to 0.785); logistic regression, 0.87 (95% CI = 0.862 to 0.870); random forest, 0.87 (95% CI = 0.862 to 0.872); deep neural network, 0.89 (95% CI = 0.882 to 0.890). As a result, we confirmed the possibility of remote triage using a wearable device. It is expected that the time required for triage can be effectively reduced by using the developed classification model of survival prediction.

In native tissues, cellular and acellular components are anisotropically organized and often aligned in specific directions, providing structural and mechanical properties for actuating biological functions. Thus, engineering alignment not only allows for emulation of native tissue structures but might also enable implementation of specific functionalities. However, achieving desired alignment is challenging, especially in three-dimensional constructs. By exploiting the elastomeric property of polydimethylsiloxane and fibrillogenesis kinetics of collagen, here we introduce a simple yet effective method to assemble and align fibrous structures in a multi-modular three-dimensional conglomerate. Applying this method, we have reconstructed the CA3-CA1 hippocampal neural circuit three-dimensionally in a monolithic gel, in which CA3 neurons extend parallel axons to and synapse with CA1 neurons. Furthermore, we show that alignment of the fibrous scaffold facilitates the establishment of functional connectivity. This method can be applied for reconstructing other neural circuits or tissue units where anisotropic organization in a multi-modular structure is desired.

Morphine is the most potent analgesic for chronic pain, but its clinical use has been limited by the opiate's innate tendency to produce tolerance, severe withdrawal symptoms and rewarding properties with a high risk of relapse. To understand the addictive properties of morphine, past studies have focused on relevant molecular and cellular changes in the brain, highlighting the functional roles of reward-related brain regions. Given the accumulated findings, a recent, emerging trend in morphine research is that of examining the dynamics of neuronal interactions in brain reward circuits under the influence of morphine action. In this review, we highlight recent findings on the roles of several reward circuits involved in morphine addiction based on pharmacological, molecular and physiological evidences.

BACKGROUND: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and sporadic Parkinson's disease (PD). Elevated kinase activity is associated with LRRK2 toxicity, but the substrates that mediate neurodegeneration remain poorly defined. Given the increasing evidence suggesting a role of LRRK2 in membrane and vesicle trafficking, here we systemically screened Rab GTPases, core regulators of vesicular dynamics, as potential substrates of LRRK2 and investigated the functional consequence of such phosphorylation in cells and in vivo. METHODS: In vitro LRRK2 kinase assay with forty-five purified human Rab GTPases was performed to identify Rab family proteins as substrates of LRRK2. We identified the phosphorylation site by tandem mass-spectrometry and confirmed it by assessing phosphorylation in the in vitro LRRK2 kinase assay and in cells. Effects of Rab phosphorylation on neurodegeneration were examined in primary cultures and in vivo by intracranial injection of adeno-associated viral vectors (AAV) expressing wild-type or phosphomutants of Rab35. RESULTS: Our screening revealed that LRRK2 phosphorylated several Rab GTPases at a conserved threonine residue in the switch II region, and by using the kinase-inactive LRRK2-D1994A and the pathogenic LRRK2-G2019S along with Rab proteins in which the LRRK2 site was mutated, we verified that a subset of Rab proteins, including Rab35, were authentic substrates of LRRK2 both in vitro and in cells. We also showed that phosphorylation of Rab regulated GDP/GTP-binding property in cells. Moreover, in primary cortical neurons, mutation of the LRRK2 site in several Rabs caused neurotoxicity, which was most severely induced by phosphomutants of Rab35. Furthermore, intracranial injection of the AAV-Rab35 -T72A or AAV-Rab35-T72D into the substantia nigra substantially induced degeneration of dopaminergic neurons in vivo. CONCLUSIONS: Here we show that a subset of Rab GTPases are authentic substrates of LRRK2 both in vitro and in cells. We also provide evidence that dysregulation of Rab phosphorylation in the LRRK2 site induces neurotoxicity in primary neurons and degeneration of dopaminergic neurons in vivo. Our study suggests that Rab GTPases might mediate LRRK2 toxicity in the progression of PD.

The underlying mechanisms of how positive emotional valence (e.g., pleasure) causes preference of an associated context is poorly understood. Here, we show that activation of astrocytic μ-opioid receptor (MOR) drives conditioned place preference (CPP) by means of specific modulation of astrocytic MOR, an exemplar endogenous Gi protein-coupled receptor (Gi-GPCR), in the CA1 hippocampus. Long-term potentiation (LTP) induced by a subthreshold stimulation with the activation of astrocytic MOR at the Schaffer collateral pathway accounts for the memory acquisition to induce CPP. This astrocytic MOR-mediated LTP induction is dependent on astrocytic glutamate released upon activation of the astrocytic MOR and the consequent activation of the presynaptic mGluR1. The astrocytic MOR-dependent LTP and CPP were recapitulated by a chemogenetic activation of astrocyte-specifically expressed Gi-DREADD hM4Di. Our study reveals that the transduction of inhibitory Gi-signaling into augmented excitatory synaptic transmission through astrocytic glutamate is critical for the acquisition of contextual memory for CPP.

Alzheimer's disease (AD) is associated with neurodegenerative changes resulting clinically in progressive cognitive and functional deficits. The only therapies are the cholinesterase inhibitors donepezil, galantamine and rivastigmine and the N-methyl-D-aspartate-receptor antagonist memantine. Donepezil acts primarily on the cholinergic system as a symptomatic treatment, but it also has potential for disease modification and may reduce the rate of progression of AD. This review explores the potential for disease modifying effects of donepezil. Several neuroprotective mechanisms that are independent of cholinesterase inhibition, are suggested. Donepezil has demonstrated a range of effects, including protecting against amyloid β, ischaemia and glutamate toxicity; slowing of progression of hippocampal atrophy; and up-regulation of nicotinic acetylcholine receptors. Clinically, early and continuous treatment with donepezil is considered to preserve cognitive function more effectively than delayed treatment. The possible neuroprotective effects of donepezil and the potential for disease pathway modification highlight the importance of early diagnosis and treatment initiation in AD.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. However, cell type-dependent transcriptional regulatory programs responsible for PD pathogenesis remain elusive. Here, we establish transcriptomic and epigenomic landscapes of the substantia nigra by profiling 113,207 nuclei obtained from healthy controls and patients with PD. Our multiomics data integration provides cell type annotation of 128,724 cis-regulatory elements (cREs) and uncovers cell type-specific dysregulations in cREs with a strong transcriptional influence on genes implicated in PD. The establishment of high-resolution three-dimensional chromatin contact maps identifies 656 target genes of dysregulated cREs and genetic risk loci, uncovering both potential and known PD risk genes. Notably, these candidate genes exhibit modular gene expression patterns with unique molecular signatures in distinct cell types, highlighting altered molecular mechanisms in dopaminergic neurons and glial cells including oligodendrocytes and microglia. Together, our single-cell transcriptome and epigenome reveal cell type-specific disruption in transcriptional regulations related to PD.

Autophagy has been implicated in innate immune responses against various intracellular pathogens. Recent studies have reported that autophagy can be triggered by pathogen recognizing sensors, including Toll-like receptors and cyclic guanosine monophosphate-adenosine monophosphate synthase, to participate in innate immunity. In the present study, we examined whether the RIG-I signaling pathway, which detects viral infections by recognizing viral RNA, triggers the autophagic process. The introduction of polyI:C into the cytoplasm, or Sendai virus infection, significantly induced autophagy in normal cells but not in RIG-I-deficient cells. PolyI:C transfection or Sendai virus infection induced autophagy in the cells lacking type-I interferon signaling. This demonstrated that the effect was not due to interferon signaling. RIG-I-mediated autophagy diminished by the deficiency of mitochondrial antiviral signaling protein (MAVS) or tumor necrosis factor receptor-associated factor (TRAF)6, showing that the RIG-I-MAVS-TRAF6 signaling axis was critical for RIG-I-mediated autophagy. We also found that Beclin-1 was translocated to the mitochondria, and it interacted with TRAF6 upon RIG-I activation. Furthermore, Beclin-1 underwent K63-polyubiquitination upon RIG-I activation, and the ubiquitination decreased in TRAF6-deficient cells. This suggests that the RIG-I-MAVS-TRAF6 axis induced K63-linked polyubiquitination of Beclin-1, which has been implicated in triggering autophagy. As deficient autophagy increases the type-I interferon response, the induction of autophagy by the RIG-I pathway might also contribute to preventing an excessive interferon response as a negative-feedback mechanism.

Tauopathy is a collective term for neurodegenerative diseases associated with pathological modifications of tau protein. Tau modifications are mediated by many factors. Recently, reactive oxygen species (ROS) have attracted attention due to their upstream and downstream effects on tauopathy. In physiological conditions, healthy cells generate a moderate level of ROS for self-defense against foreign invaders. Imbalances between ROS and the anti-oxidation pathway cause an accumulation of excessive ROS. There is clear evidence that ROS directly promotes tau modifications in tauopathy. ROS is also highly upregulated in the patients' brain of tauopathies, and anti-oxidants are currently prescribed as potential therapeutic agents for tauopathy. Thus, there is a clear connection between oxidative stress (OS) and tauopathies that needs to be studied in more detail. In this review, we will describe the chemical nature of ROS and their roles in tauopathy.

Terahertz (THz) technology has become more widespread due to its diverse range of potential applications, particularly when combined with various functional metamaterials using cutting-edge nanotechnology techniques. In this report, we introduce a highly improved THz imaging technology by comparing complementary metamaterials intuitively based on Babinet’s principle. The THz reflectance spectra for the complementary metamaterials exhibit a significant and distinct association with the polarization angle. Four different polarization angles and metamaterial pattern geometries were tested for the reflectance imaging of a target image pattern. Field enhancement on the metamaterial surface was also investigated using finite element simulations to support the experimental results. Optimizing the metamaterial based on the experimental and calculation results led to high image contrast and quality. The proposed label-free imaging platform was then employed to produce clear contrast images for mouse brain tissue and HEK-293 cells, thus highlighting the potential application of this system to real biological samples.

BACKGROUND: The objective of our study was to analyze the neuroprotective effects of ginsenoside derivatives Rb1, Rb2, Rc, Rd, Rg1, and Rg3 against glutamate-mediated neurotoxicity in HT22 hippocampal mouse neuron cells. METHODS: efficacy of neuroprotection was evaluated using the Mongolian gerbil of ischemic brain injury model. RESULT: data indicated that Rb2 treatment (10 mg/kg) significantly diminished the number of degenerated neurons. CONCLUSION: Our results suggest that Rb2 possesses neuroprotective properties that suppress glutamate-induced neurotoxicity. The molecular mechanism of Rb2 is by suppressing the MAPKs activity and AIF translocation.

An ongoing pandemic of coronavirus disease 2019 (COVID-19) is now the greatest threat to global public health. Herbal medicines and their derived natural products have drawn much attention in the treatment of COVID-19, but the detailed mechanisms by which natural products inhibit SARS-CoV-2 have not been elucidated. Here, we show that platycodin D (PD), a triterpenoid saponin abundant in Platycodon grandiflorum (PG), a dietary and medicinal herb commonly used in East Asia, effectively blocks the two main SARS-CoV-2 infection routes via lysosome- and transmembrane protease serine 2 (TMPRSS2)-driven entry. Mechanistically, PD prevents host entry of SARS-CoV-2 by redistributing membrane cholesterol to prevent membrane fusion, which can be reinstated by treatment with a PD-encapsulating agent. Furthermore, the inhibitory effects of PD are recapitulated by the pharmacological inhibition or gene silencing of NPC1, which is mutated in patients with Niemann-Pick type C (NPC) displaying disrupted membrane cholesterol distribution. Finally, readily available local foods or herbal medicines containing PG root show similar inhibitory effects against SARS-CoV-2 infection. Our study proposes that PD is a potent natural product for preventing or treating COVID-19 and that briefly disrupting the distribution of membrane cholesterol is a potential novel therapeutic strategy for SARS-CoV-2 infection.

Abstract Abnormal aggregation of β-amyloid (Aβ) peptides is a major hallmark of Alzheimer’s disease (AD). In spite of numerous attempts to prevent the β-amyloidosis, no effective drugs for treating AD have been developed to date. Among many candidate chemicals, methylene blue (MB) has proved its therapeutic potential for AD in a number of in vitro and in vivo studies; but the result of recent clinical trials performed with MB and its derivative was negative. Here, with the aid of multiple photochemical analyses, we first report that photoexcited MB molecules can block Aβ 42 aggregation in vitro . Furthermore, our in vivo study using Drosophila AD model demonstrates that photoexcited MB is highly effective in suppressing synaptic toxicity, resulting in a reduced damage to the neuromuscular junction (NMJ), an enhanced locomotion, and decreased vacuole in the brain. The hindrance effect is attributed to Aβ 42 oxidation by singlet oxygen ( 1 O 2 ) generated from photoexcited MB. Finally, we show that photoexcited MB possess a capability to disaggregate the pre-existing Aβ 42 aggregates and reduce Aβ-induced cytotoxicity. Our work suggests that light illumination can provide an opportunity to boost the efficacies of MB toward photodynamic therapy of AD in future.