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Institute of Neuroscience, NYMU
Yun-Chia Chou Associate professor
Laboratory of Brain Disease Mechanism
image Yun-Chia Chou   Associate professor
Tel : 886-2-2826-7157
Fax : 886-2-2820-0259

Chang, C.-H. Cheng, C.-F.
image The neurotoxicity of glutamate (Glu), and to a lesser extent related excitatory amino acids (EAAs), plays an important role in the pathogenesis of neurological disorders, including aging-related brain diseases. Normally these EAAs mediate excitatory neurotransmission. When released in excess, which occurs during neuronal injury, Glu activate both ionotropic and metabotropic Glu receptors which, in turn, causes pathologic elevation of intracellular calcium concentrations. Such calcium activates a wide range of catabolic enzymes and triggers the release of free radicals, thus impairing cellular function, membrane structure and cytoskeleton and eventually leading to cell death.
Work in this laboratory has been focused on the factors modulating Glu-induced toxicity to hippocampal cells, namely neurons and astrocytes, in primary cultures. We previously demonstrated that cholesterol deficiency exacerbated Glu-induced cytotoxicity to hippocampal astrocytes, but not to neurons, in primary cultures. Moreover, cholesterol deprivation provokes morphological changes, impairs cortical actin ring and stimulates ERK phosphorylation in astrocytes exclusively. The experimental manipulation increses the activity of the Glu transporter, while reducing the expression of glutamine synthetase. It is likely that cholesterol deficiency leads to a buildup of a concentration gradient favoring Glu efflux. The breakdown of the cortical actin barrier further accelerates the accumulation of extracellular Glu, thereby exacerbating the excitotoxic cascade.
Accordingly, it is likely that the detrimental effect of cholesterol deprivation may, in part, arise from an impairment of the signaling pathways associated with actin stability and Glu homeostasis. As noted, lipid rafts and certain membrane-bound signaling molecules are linked to a dynamic filamentous actin network. Compelling evidence indicates that deprivation of cellular cholesterol impairs the integrity of lipid raft, the cholesterol-enriched microdomain within plasma membrane, and in turn leads to dysfunction of raft-associated proteins and disruption of actin ring. Such notion has been supported by our finding that cholesterol deprivation hampered the translocation of Rho and Rac-1 into membrane of astrocytes. In the future, we shall explore the mechanism by which cholesterol deficiency may impair raft-related signaling molecules, such as Rho GTPase, in an astrocyte-specific manner.
image Cholesterol, an integral component of all eukaryotic cell membranes, is essential for normal cellular functions. It is found in particularly high concentrations in neural tissue due to the immense lipid demand for growth and maintenance of neurites and for synapse formation. Shortage of cholesterol affects the function of brain cells and has been implicated in the pathogenesis of several neurodegenerative disorders.
It is conceivable that findings from our work will provide new insight into our understanding in cholesterol modulation of brain function. Growing evidence indicates that Aβ-induced neurotoxicity is secondary to impaired astrocytic function in the support of neuronal viability. It is anticipated that results from our future work will facilitate our ability to develop an effective therapeutic strategy for brain diseases related to cholesterol insufficiency, namely Alzheimer’s disease.
image Mechanistic study of cholesterol deficiency aggravating glutamate-induced cytoxicity
image Mechanistic study of cholesterol deficiency modulating cell viability
image Huang, Z.-H, Wu, H.-J., Yeh, C.-C., Chou ,Y.-C. and Chang, Y.-C. (2006) Dendritic spines of developing rat cortical neurons in culture. Chinese J. Physiol. 49:1-7
image Chou, Y.-C., Lin, S.-B, Tsai, l.H., Tsai, H.-I., and Lin, C.M. (2003) Cholesterol deficiency increases the vulnerability of hippocampal glia in primary culture to glutamate-induced excitotoxicity. Neurochem. Intl. 43:197-209.
image Lin, Y.-C., Huang, Z.-H., Jan, I.-S., Yeh, C.-C., Wu, H.-J., Chou, Y.-C., and Chang, Y.-C. (2002) Development of excitatory synapses in cultured neurons dissociated from the cortices of rat embryos and rat pups at birth. J. Neurosci. Res. 67:484-493.
image Chou, Y.-C., Yu, S., and Lin, S.B. (1999) Cholesterol depletion exacerbates glutamate-induced cell death in hippocampal cultures. Soc. Neurosci. Abstr. 23:1142.
image Chiang, A.-N., Chang, C.-P., Chou, Y.-C., Huang, K.-Y., and Hu, H.-H. (1999) Differential distribution of apolipoprotein E in young and aged spontaneously hypertensive and stroke-prone rats. J. Hypertension 17:793-800.
image Chou, Y.-C. (1998) Corticosterone exacerbates cyanide-induced cell death in hippocampal cultures: role of astrocytes. Neurochem. Intl. 32:219-226.
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