| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2003: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
Immuno-inflammatory process in association with reactive gliosis has been suggested to play an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS). We have shown the important role of CD40, which has been investigated as a costimulatory molecule in the field of immunology, in the pathogenesis of central nervous system (CNS) diseases.
CD40 was expressed in neurons, astrocytes, and microglia in vitro and the expression in neurons increased in association with the differentiation. Though CD40 was predominantly expressed in neurons in normal adult CNS, the level of expression increased in reactive glial cells in the pathological conditions such as injured spinal cord, brain of APP-transgenic (Tg) mice model of AD, and spinal cord of SOD-Tg mice model of ALS. Inflammatory molecules such as TNF-α, iNOS, cyclooxygenase-2 (COX-2) were induced in glial cells by the stimulation of CD40 and, in addition, these levels were affected by CD100 pathway. In these inflammatory molecules, co-expression of CD40 and COX-2 was predominantly seen in reactive glial cells in those Tg mice models in vivo. CD40 stimulation in primary mixed spinal cord cultures caused motor neuron loss that was protected by selective COX-2 inhibitor. Though the neuronal loss was not induced in the cultures derived from CD40-defficient mice, it occurred when the wild type glial cells were added onto the cultures. Thus, these results suggested that CD40, which is up-regulated in reactive glial cells, participates in neuron loss via induction of COX-2.
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