THERAPEUTIC POTENTIAL OF NEUROTROPHINS IN ALZHEIMERS

摘要：阿尔茨海默病(AD)与退行性疾病有关 大脑中各种特定神经细胞群的变化和丢失。 由于神经营养因子调节生存和分化功能 对于神经元，它们可能为发展有效的 治疗阿尔茨海默病。通过防止或减轻神经元退化， 神经营养因子可能会减缓或阻止疾病的进展。 以及相关的认知障碍。基于它的预防能力 实验性胆碱能神经元的退行性改变 在大鼠和猴子的病变中，神经生长因子(NGF)目前 被认为是治疗阿尔茨海默病的实验性药物。神经生长因子在心脏疾病中的价值 阿尔茨海默病的治疗受到其对前脑胆碱能选择性的限制 神经元。NGF同源物，脑源性神经营养因子(BDNF)， 神经营养因子-3(NT-3)和神经营养因子-4/5(NT-4/5)，形成该家族 神经营养因子，影响许多脑神经元群体。分析 它们的神经营养作用正在进行中。它们似乎有不同的， 但部分重叠的活性光谱在选定的种群上 中枢神经元。旨在确定最有用的神经营养素 分子，我们建议制备神经营养因子，神经营养因子突变体， 修饰的神经营养因子，以及用于此的新的神经营养因子 计划项目。新分子的初步特征将在 受体分析和细胞培养中的分析。生物活性 通过体外测试选择的分子随后将在体内进行测试 模拟阿尔茨海默病退行性改变的大鼠脑损伤模型 大脑。可使用的神经退行性变模型包括隔-海马区 切断海马伞后的胆碱能和GABA能神经元，皮质- 切断角束后的海马神经元，以及 扣带回切断后丘脑皮质神经元。另外两个项目是 建议。为了评估神经营养因子的治疗潜力，我们计划 为了测量脑组织对神经营养因子的反应性 新的体外试验。我们建议进一步分析治疗方法 小分子K-252a和K-252b早期化合物的势能 显示可增强NT-3的作用。希望这些研究 将导致神经营养因子变体的鉴定，其他 神经营养因子或小分子最有用的进一步 作为阿尔茨海默病治疗药物的研究进展。该计划项目 加入知名学术和工业科学家的行列，拥有 在药理开发方面的先前合作 开发AD和AD有效治疗方法的神经营养因子 认知疾病。

Summary: Alzheimer's disease (AD) is associated with degeneration changes and loss of various specific populations of neurons in the brain. Since neurotrophic factors regulate survival and differentiated functions of neurons, they may provide avenues for the development of effective treatment for AD. By preventing or attenuating neuronal degeneration, neurotrophic factors may slow down or stop the progression of the disease and associated cognitive disturbances. Based on its ability to prevent degenerative changes of cholinergic neurons induced by experimental lesions in rats and monkeys, nerve growth factor (NGF) is presently considered as experimental treatment for AD. The value of NGF in the treatment of AD is limited by its selectivity for forebrain cholinergic neurons. NGF homologs, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5), forming the family of neurotrophins, affect many populations of brain neurons. The analysis of their neurotrophic actions is ongoing. They appear to have different, but partially overlapping spectra of activity on select populations of central neurons. Aiming at identifying the most useful neurotrophin molecules, we propose to prepare neurotrophins, neurotrophin mutants, modified neurotrophins, as well as novel neurotrophic factors for this program project. The new molecules will be characterized initially in receptor assays and in cell culture assays. Biologically active molecules selected by the in vitro assays will then be tested in vivo in rat brain lesion models mimicking degenerative changes occurring in AD brains. Models of neurodegeneration to be used include septo-hippocampal cholinergic and GABAergic neurons after fimbrial transection, cortico- hippocampal neurons after transections of the angular bundle, and thalamo-cortical neurons after cingulotomy. Two additional projects are proposed. To assess the therapeutic potential of neurotrophins, we plan to measure the responsiveness of brain tissue to neurotrophins using a novel ex vivo assay. We propose to further analyze the therapeutic potential of the small molecules K-252a and K-252b, compounds earlier shown to potentiate the action of NT-3. It is hoped that the studies will lead to the identification of neurotrophin variants, other neurotrophic factors or small molecules most useful for further development as therapeutics in Alzheimer's disease. The program project joins established academic and industrial scientists with a record of previous collaboration in the pharmacological exploitation of neurotrophic factors for developing effective treatment for AD and cognitive diseases.