• Molecules and Cells
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• v.40 no.11
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• pp.864-870
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• 2017

The uncoupling protein 4 (ucp-4) gene is involved in age-dependent neurodegeneration in C. elegans. Therefore, we aimed to investigate the mechanism underlying the association between mitochondrial uncoupling and neurodegeneration by examining the effects of uncoupling agents and ucp-4 overexpression in C. elegans. Treatment with either DNP or CCCP improved neuronal defects in wild type during aging. Uncoupling agents also restored neuronal phenotypes of ucp-4 mutants to those exhibited by wild type, while ucp-4 overexpression attenuated the severity of age-dependent neurodegeneration. Neuronal improvements were further associated with reductions in mitochondrial membrane potentials. However, these age-dependent neuroprotective effects were limited in mitophagy-deficient mutant, pink-1, background. These results suggest that membrane uncoupling can attenuate age-dependent neurodegeneration by stimulating mitophagy.

• BMB Reports
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• v.43 no.4
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• pp.225-232
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• 2010

Parkinson's Disease (PD) is a common neurodegenerative disease characterized by the progressive degeneration of nigrostriatal dopaminergic (DA) neurons. Although the causative factors of PD remain elusive, many studies on PD animal models or humans suggest that glial activation along with neuroinflammatory processes contribute to the initiation or progression of PD. Additionally, several groups have proposed that dysfunction of the blood-brain barrier (BBB) combined with infiltration of peripheral immune cells play important roles in the degeneration of DA neurons. However, these neuroinflammatory events have only been investigated separately, and the issue of whether these phenomena are neuroprotective or neurotoxic remains controversial. We here review the current knowledge regarding the functions of these neuroinflammatory processes in the brain. Finally, we describe therapeutic strategies for the regulation of neuroinflammation with the goal of improving the symptoms of PD.

• Journal of Interdisciplinary Genomics
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• v.2 no.1
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• pp.1-4
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• 2020

Recent advances in magnetic resonance imaging and identification of causative genes led to the recognition of a new group of disorders named neurodegeneration with brain iron accumulation (NBIA). NBIA is a group of inherited disorders characterized by abnormal iron deposition in the brain, usually in the basal ganglia. The disorder shares the clinical features of movement disorders and is accompanied by varying degrees of neuropsychiatric abnormalities. In this review, the causative genes, clinical presentations, neuroimaging features, and pathological findings are summarized.

• BMB Reports
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• v.42 no.8
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• pp.475-481
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• 2009

Emerging data demonstrate pivotal roles for brain insulin resistance and insulin deficiency as mediators of cognitive impairment and neurodegeneration, particularly Alzheimer's disease (AD). Insulin and insulin-like growth factors (IGFs) regulate neuronal survival, energy metabolism, and plasticity, which are required for learning and memory. Hence, endogenous brain-specific impairments in insulin and IGF signaling account for the majority of AD-associated abnormalities. However, a second major mechanism of cognitive impairment has been linked to obesity and Type 2 diabetes (T2DM). Human and experimental animal studies revealed that neurodegeneration associated with peripheral insulin resistance is likely effectuated via a liver-brain axis whereby toxic lipids, including ceramides, cross the blood brain barrier and cause brain insulin resistance, oxidative stress, neuro-inflammation, and cell death. In essence, there are dual mechanisms of brain insulin resistance leading to AD-type neurodegeneration: one mediated by endogenous, CNS factors; and the other, peripheral insulin resistance with excess cytotoxic ceramide production.

• Molecules and Cells
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• v.40 no.9
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• pp.613-620
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• 2017

The most common form of senile dementia is Alzheimer's disease (AD), which is characterized by the extracellular deposition of amyloid ${\beta}-peptide$ ($A{\beta}$) plaques and the intracellular formation of neurofibrillary tangles (NFTs) in the cerebral cortex. Tau abnormalities are commonly observed in many neurodegenerative diseases including AD, Parkinson's disease, and Pick's disease. Interestingly, tau-mediated formation of NFTs in AD brains shows better correlation with cognitive impairment than $A{\beta}$ plaque accumulation; pathological tau alone is sufficient to elicit frontotemporal dementia, but it does not cause AD. A growing amount of evidence suggests that soluble $A{\beta}$ oligomers in concert with hyperphosphorylated tau (pTau) serve as the major pathogenic drivers of neurodegeneration in AD. Increased $A{\beta}$ oligomers trigger neuronal dysfunction and network alternations in learning and memory circuitry prior to clinical onset of AD, leading to cognitive decline. Furthermore, accumulated damage to mitochondria in the course of aging, which is the best-known nongenetic risk factor for AD, may collaborate with soluble $A{\beta}$ and pTau to induce synapse loss and cognitive impairment in AD. In this review, I summarize and discuss the current knowledge of the molecular and cellular biology of AD and also the mechanisms that underlie $A{\beta}-mediated$ neurodegeneration.

• Journal of Korean Neurosurgical Society
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• v.38 no.4
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• pp.287-292
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• 2005

Objective : Kainic acid[KA] enhances the expression of nitric oxide synthase, increases nitric oxide[NO], and thus evokes epileptic convulsion, which results in neuronal damage in the rat brain. NO may stimulate cyclooxygenase type-2 [COX-2] activity, thus producing seizure and neuronal injury, but it has also been reported that KA-induced seizure and neurodegeneration are aggravated on decreasing the COX-2 level. This study was undertaken to investigate whether the suppression of NO using the NOS inhibitor, N-nitro-L-arginine methyl ester[L-NAME], suppresses or enhances the activity of COX-2. Methods : Silver impregnation and COX-2 immunohistochemical staining were used to localize related pathophysiological processes in the rat forebrain following KA-induced epileptic convulsion and L-NAME pretreatment. Post-injection survival of the rat was 1, 2, 3days and 2months, respectively. Results : After the systemic administration of KA in rats, neurodegeneration increased with time in the cornu ammonis [CA] 3, CA 1 and amygdala, as confirmed by silver impregnation. On pretreating L-NAME, KA-induced neuronal degeneration decreased. COX-2 enzyme activities increased after KA injection in the dentate gyrus, CA 3, CA 1, amygdala and pyriform cortex, as determined by COX-2 staining. L-NAME pretreatment prior to KA-injection, caused COX-2 activities to increase compared with KA- injection only group by 1day and 2days survival time point. Conclusion : These results suggest that L-NAME has a neuroprotective effect on KA-induced neuronal damage, especially during the early stage of neurodegeneration.

• Journal of Veterinary Science
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• v.22 no.1
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• pp.7.1-7.13
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• 2021

Background: Niemann-Pick disease type C (NPC) is caused by the mutation of NPC genes, which leads to the abnormal accumulation of unesterified cholesterol and glycolipids in lysosomes. This autosomal recessive disease is characterized by liver dysfunction, hepatosplenomegaly, and progressive neurodegeneration. Recently, the application of induced neural stem cells (iNSCs), converted from fibroblasts using specific transcription factors, to repair degenerated lesions has been considered a novel therapy. Objectives: The therapeutic effects on NPC by human iNSCs generated by our research group have not yet been studied in vivo; in this study, we investigate those effects. Methods: We used an NPC mouse model to efficiently evaluate the therapeutic effect of iNSCs, because neurodegeneration progress is rapid in NPC. In addition, application of human iNSCs from NPC patient-derived fibroblasts in an NPC model in vivo can give insight into the clinical usefulness of iNSC treatment. The iNSCs, generated from NPC patientderived fibroblasts using the SOX2 and HMGA2 reprogramming factors, were transplanted by intracerebral injection into NPC mice. Results: Transplantation of iNSCs showed positive results in survival and body weight change in vivo. Additionally, iNSC-treated mice showed improved learning and memory in behavior test results. Furthermore, through magnetic resonance imaging and histopathological assessments, we observed delayed neurodegeneration in NPC mouse brains. Conclusions: iNSCs converted from patient-derived fibroblasts can become another choice of treatment for neurodegenerative diseases such as NPC.

• Journal of the Korean Applied Science and Technology
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• v.36 no.3
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• pp.804-812
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• 2019

The purpose of this study was to investigate the effects of different types of exercise training on neurodegeneration and cognitive function in mice with impaired glucose tolerance (IGT). Thirty-six male C57BL/6 mice were randomly assigned to the control (CO, n = 9) and impaired glucose tolerance (IGT, n = 27) groups. The IGT group consumed 45% high fat diet for 4 weeks and received 40 mg/kg of streptozotocin twice in the lower abdomen to induce IGT. After the IGT induction period, the IGT group was subdivided into IGT + sedentary (IGT, n = 9), IGT + endurance exercise (IGTE, n = 9), and IGT + resistance exercise (IGTR, n = 9). The IGTE and IGTR groups performed treadmill and ladder climbing exercises 5 times per week for 8 weeks, respectively. Fasting glucose and glycated hemoglobin (HbA1c) levels were significantly higher in IGT group than in CO, IGTE, and IGTR groups (p < 0.05). HOMA-IR was significantly higher in IGT group than CO group (p < 0.05). Hippocampal catalase (CAT) was significantly lower in IGT group than in CO group (p < 0.05), while beta-amyloid ($A{\beta}$) was significantly higher in IGT group than in CO group (p < 0.05). Hippocampal tau was significantly higher in IGT group than in CO, IGTE, and IGTR groups (p < 0.05). The Y-maze test performance for cognitive function was significantly lower in IGT group than in CO, IGTE, and IGTR groups (p <0.05). These results suggest that IGT induces neurodegeneration and negatively affects cognitive function, while regular exercise may be effective in alleviating neurodegeneration and cognitive decline regardless of exercise type.

• Proceedings of the Microbiological Society of Korea Conference
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• 2009.05a
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• pp.144-144
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• 2009

• BMB Reports
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• v.42 no.6
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• pp.324-330
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• 2009

Autophagy is a bulk lysosomal degradation process important in development, differentiation and cellular homeostasis in multiple organs. Interestingly, neuronal survival is highly dependent on autophagy due to its post-mitotic nature, polarized morphology and active protein trafficking. A growing body of evidence now suggests that alteration or dysfunction of autophagy causes accumulation of abnormal proteins and/or damaged organelles, thereby leading to neurodegenerative disease. Although autophagy generally prevents neuronal cell death, it plays a protective or detrimental role in neurodegenerative disease depending on the environment. In this review, the two sides of autophagy will be discussed in the context of several neurodegenerative diseases.