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Lee, Hyun,Lee, Jong Kil,Bae, Yong Chul,Yang, Song Hyun,Okino, Nozomu,Schuchman, Edward H.,Yamashita, Tadashi,Bae, Jae-Sung,Jin, Hee Kyung Korean Society for Molecular and Cellular Biology 2014 Molecules and cells Vol.37 No.2
In several lysosomal storage disorders, including Niemann-Pick disease Type C (NP-C), sphingolipids, including glycosphingolipids, particularly gangliosides, are the predominant storage materials in the brain, raising the possibility that accumulation of these lipids may be involved in the NP-C neurodegenerative process. However, correlation of these accumulations and NP-C neuropathology has not been fully characterized. Here we derived NP-C mice with complete and partial deletion of the Siat9 (encoding GM3 synthase) gene in order to investigate the role of ganglioside in NP-C pathogenesis. According to our results, NP-C mice with homozygotic deletion of GM3 synthase exhibited an enhanced neuropathological phenotype and died significantly earlier than NP-C mice. Notably, in contrast to complete depletion, NP-C mice with partial deletion of the GM3 synthase gene showed ameliorated NP-C neuropathology, including motor disability, demyelination, and abnormal accumulation of cholesterol and sphingolipids. These findings indicate the crucial role of GM3 synthesis in the NP-C phenotype and progression of CNS pathologic abnormality, suggesting that well-controlled inhibition of GM3 synthesis could be used as a therapeutic strategy.
Lee, Jong Kil,Jin, Hee Kyung,Park, Min Hee,Kim, Bo-ra,Lee, Phil Hyu,Nakauchi, Hiromitsu,Carter, Janet E.,He, Xingxuan,Schuchman, Edward H.,Bae, Jae-sung The Rockefeller University Press 2014 The Journal of experimental medicine Vol.211 No.8
<P>In Alzheimer’s disease (AD), abnormal sphingolipid metabolism has been reported, although the pathogenic consequences of these changes have not been fully characterized. We show that acid sphingomyelinase (ASM) is increased in fibroblasts, brain, and/or plasma from patients with AD and in AD mice, leading to defective autophagic degradation due to lysosomal depletion. Partial genetic inhibition of ASM (<I>ASM<SUP>+/−</SUP></I>) in a mouse model of familial AD (FAD; <I>amyloid precursor protein</I> [<I>APP</I>]<I>/presenilin 1</I> [<I>PS1</I>]) ameliorated the autophagocytic defect by restoring lysosomal biogenesis, resulting in improved AD clinical and pathological findings, including reduction of amyloid-β (Aβ) deposition and improvement of memory impairment. Similar effects were noted after pharmacologic restoration of ASM to the normal range in APP/PS1 mice. Autophagic dysfunction in neurons derived from FAD patient induced pluripotent stem cells (iPSCs) was restored by partial ASM inhibition. Overall, these results reveal a novel mechanism of ASM pathogenesis in AD that leads to defective autophagy due to impaired lysosomal biogenesis and suggests that partial ASM inhibition is a potential new therapeutic intervention for the disease.</P>
Lee, Jong Kil,Schuchman, Edward H,Jin, Hee Kyung,Bae, Jae-sung AlphaMed Press 2012 Stem cells Vol.30 No.7
<P>Microglia have the ability to eliminate amyloid β (Aβ) by a cell-specific phagocytic mechanism, and bone marrow (BM) stem cells have shown a beneficial effect through endogenous microglia activation in the brains of Alzheimer's disease (AD) mice. However, the mechanisms underlying BM-induced activation of microglia have not been resolved. Here we show that BM-derived mesenchymal stem cells (MSCs) induced the migration of microglia when exposed to Aβ in vitro. Cytokine array analysis of the BM-MSC media obtained after stimulation by Aβ further revealed elevated release of the chemoattractive factor, CCL5. We also observed that CCL5 was increased when BM-MSCs were transplanted into the brains of Aβ-deposited AD mice, but not normal mice. Interestingly, alternative activation of microglia in AD mice was associated with elevated CCL5 expression following intracerebral BM-MSC transplantation. Furthermore, by generating an AD-green fluorescent protein chimeric mouse, we ascertained that endogenous BM cells, recruited into the brain by CCL5, induced microglial activation. Additionally, we observed that neprilysin and interleukin-4 derived from the alternative microglia were associated with a reduction in Aβ deposition and memory impairment in AD mice. These results suggest that the beneficial effects observed in AD mice after intracerebral SC transplantation may be explained by alternative microglia activation. The recruitment of the alternative microglia into the brain is driven by CCL5 secretion from the transplanted BM-MSCs, which itself is induced by Aβ deposition in the AD brain.</P>
Perioperative critical care management for patients with aneurysmal subarachnoid hemorrhage
Kiwon Lee,H. Alex Choi,Nancy Edwards,Tiffany Chang,Robert N. Sladen 대한마취통증의학회 2014 Korean Journal of Anesthesiology Vol.67 No.2
Despite significant regional and risk factor-related variations, the overall mortality rate in patients suffering from aneurysmal subarachnoid hemorrhage (SAH) remains high. Compared to ischemic stroke, which is typically irreversible, hemorrhagic stroke tends to carry a higher mortality, but patients who do survive have less disability. Technologies to monitor and treat complications of SAH have advanced considerably in recent years, but good long-term functional outcome still depends on prompt diagnosis, early aggressive management, and avoidance of premature withdrawal of support. Endovascular procedures and open craniotomy to secure a ruptured aneurysm represent some of the numerous critical steps required to achieve the best possible result. In this review, we have attempted to provide a contemporary, evidence-based outline of the perioperative critical care management of patients with SAH. This is a challenging and potentially fatal disease with a wide spectrum of severity and complications and an often protracted course. The dynamic nature of this illness, especially in its most severe forms, requires considerable flexibility in clinician management, especially given the panoply of available treatment modalities. Judicious hemodynamic monitoring and adaptive therapy are essential to respond to the fluctuating nature of cerebral vasospasm and the varying oxygen demands of the injured brain that may readily induce acute or delayed cerebral ischemia.
Nonmarrow Hematopoiesis Occurs in a Hyaluronic-Acid-Rich Node and Duct System in Mice
Hwang, Sunhee,Lee, Seung J.,Park, Sang H.,Chitteti, Brahmananda R.,Srour, Edward F.,Cooper, Scott,Hangoc, Giao,Broxmeyer, Hal E.,Kwon, Byoung S. Mary Ann Liebert 2014 STEM CELLS AND DEVELOPMENT Vol.23 No.21
<P>A hyaluronic-acid-rich node and duct system (HAR-NDS) was found on the surface of internal organs of mice, and inside their blood and lymph vessels. The nodes (HAR-Ns) were filled with immune cells of the innate system and were especially enriched with mast cells and histiocytes. They also contained hematopoietic progenitor cells (HPCs), such as granulocyte-macrophage, erythroid, multipotential progenitors, and mast cell progenitors (MCPs). MCPs were the most abundant among the HPCs in HAR-Ns. Their frequency was fivefold higher than that of the MCPs in bone marrow. In addition, the system contained pluripotent stem cells (PSCs) capable of producing CD45(-)Flk1(+) hemangioblast-like cells, which subsequently generated various types of HPCs and differentiated blood cells. Although HAR-Ns did not appear to harbor enough number of cells capable of long-term reconstitution or short-term radioprotection of lethally irradiated recipients, bone marrow cells were able to engraft in the HAR-NDS and reconstitute hematopoietic potentials of the system. PSCs and HPCs were consistently found in intravenous, intralymphatic, and intestinal HAR-ND. We infer that PSCs and HPCs reside in the HAR-ND and that this novel system may serve as an alternative means to traffic immature and mature blood cells throughout the body.</P>