Effects of cholesterol and glia-derived lipoproteins on survival, growth and synaptic differentiation of highly purified neurons from different regions of the mouse brain

阿尔茨海默病（AD）是由特定脑区的突触和神经元丢失引起的，但其潜在机制仍不清楚。我们提出了一个新的假设，为什么神经元只出现在特定的区域。我们对高度纯化的神经元（无胶质和无血清培养物）的研究表明，胆固醇的加入会使神经元退化，并且这种程度具有明显的区域特异性。这表明神经变性患者至少部分是由胆固醇供应不足引起的，并且特定脑区域的损伤扩大了局部神经元对胶质源性胆固醇的依赖性。与AD有关的变化可能改变神经元中的胆固醇水平，从而导致突触和神经元的逐渐丧失。我们项目的目的就是检验这个假设。我们将从小鼠大脑的不同物质中纯化神经元，并在无胆固醇培养条件下测定它们的存活率和生长率以及突触分化。然后研究了胆固醇和载脂蛋白E亚型的脂蛋白对神经元的影响。在未来，我们计划测试其他AD相关的变化，影响神经元胆固醇代谢细胞从合适的转基因小鼠。我们的项目应该有助于阐明神经变性和脑胆固醇代谢紊乱之间可能的联系。

Alzheimer´s disease (AD) is caused by a loss of synapses and neurons in specific brain regions, but the underlying mechanisms are still unknown. We propose a novel hypothesis as to why neurons occur only in specific regions. Our studies of highly purified neurons (glia- and serum-free cultures) showed that neurons degenerate addition of cholesterol and that the degree of this is remarkably region-specific. This suggests that the neurodegeneration patient is caused at least in part by an insufficient supply with cholesterol and that the damage in a specific brain area scales the dependence of local neurons on glia-derived cholesterol. The changes implicated in AD may change the cholesterol level in neurons thus cause a gradual loss of synapses and neurons. The aim of our project is to test this hypothesis. We will purify neurons from different things of the mouse brain and determine their survival and growth rates synaptic differentiation under cholesterol-free culture conditions. Then we study effects of cholesterol and lipoproteins harboring isoforms of apolipoprotein E on neurons. In the future, we plan to test other AD-related changes that affect the neuronal cholesterol metabolism cells from suitable transgenic mice. Our project should help to elucidate possible links between neurodegeneration and a disturbance in brain cholesterol metabolism.