| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
In the formation of neuronal network, morphology of individual neuron plays an important role. Mutations in presenilin 1 (PS1) are highly related to familial Alzheimer's disease (AD). We examined the effects of PS1 on neuronal morphology using SH-SY5Y cells. Overexpression of dominant-negative PS1 induced impairment of neurite formation, while those of wild-type and AD-related mutant PS1 did not change cellular morphology compared with native cells. Actin cytoskeleton-related proteins, such as Wiskott-Aldrich syndrome protein (N-WASP), were decreased only in cells expressing dominant-negative PS1. Therefore, PS1 may be involved in neuritogenesis and morphological change in SH-SY5Y cells. Furthermore, we examined the expression levels and distributions of actin cytoskeleton-related proteins, such as N-WASP, WASP family verprolin-homologous protein (WAVE) in the rat brain during postnatal development. These factors were progressively increased during development, and seemed to exist in t
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he synapse-rich areas. Thus, N-WASP and WAVE may participate in normal brain development and synaptic plasticity by regulating the actin cytoskeleton. Occlusion of the middle cerebral artery (MCA) and reperfusion caused behavioral dysfunction with massive damage of neuronal network. We examined the effects of transplantation of rat cultured microglia, mouse embryonic stem (ES) cells or ES cell-derived neuron-like (ES-N) cells on behavioral function in ischemic rats. By the transplantation, focal ischemia-induced behavioral dysfunction was significantly inhibited. The effective improvement of behavioral dysfunction may be due to the neuroprotective effect of exogenous microglia and the recovery of dopaminergic neuronal function by the transplantation of ES and ES-N cells. To investigate a transplantation strategy for Parkinson's disease (PD), we assessed whether double-transplants in the striatum (ST) and substantia nigra (SN), or ST and subthalamic nucleus (STN) induce functional recovery in 6-hydroxydopamine-lesioned rats. Drug-induced rotation was significantly reduced by transplantation of mouse ES-N into the ST, but not the STN or SN alone. Double-transplantation was also effective at recovering rotational behavior. These results suggest that both the involvement of ST and as a place of transplantation and the number of ES-N are essential factors for efficacy on hemiparkinsonian behaviors. DJ-1 has recently been shown to be responsible for onset of familial PD, PARK7. Using 6-hydroxydopamine-lesioned rats, we further found that the simultaneous and/or post injection of recombinant wild type, but not mutant human DJ-1 had neuroprotective effect. Less
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