THERAEUTIC POTENTIAL-NEUROTROPHINS/ALZHEIMER'S DISEASE

阿尔茨海默病(AD)与退行性变化和 大脑中各种神经元种群的丧失。自神经营养不良 调节神经元存活和功能维持的因子，如 这些因素可能为有效治疗的发展提供途径。 对于AD。通过预防或减轻神经元变性、神经营养 各种因素可能会减缓或阻止疾病的进展， 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 在大鼠和猴子的损伤中，神经生长因子(NGF)目前 被认为是AD的实验性治疗。这样做的一个具体目的是 应用，关系到NGF的长期效果和可行性 缓释植入物将提供更多有价值的信息 神经生长因子的临床应用。然而，NGF在AD治疗中的价值 受到其对前脑胆碱能神经元的特异性的限制。这个 新近发现的脑源性神经营养因子的同系物 脑源性神经营养因子(BDNF)和神经营养因子-3(NT-3)，建立了神经营养因子家族。 神经营养因子。这些神经营养因子影响各种外周和 中枢神经元及其在某些神经元群体中的作用重叠 但对其他人来说却不同。最近的发现，为这一点提供了基础 应用程序，表示对 神经营养因子对其生物学活性和特异性的影响 作用于神经元群体的子集。因此，建议将 通过以下方法制备神经营养因子的修饰分子形式 重组表达或通过特定的蛋白酶处理。生物学 这些修饰的神经营养因子的作用将被表征。 最初是在神经营养素受体分析和细胞培养中 生物活性修饰神经营养因子 体外测试将在大鼠脑损伤模型中进行体内测试 模仿AD大脑中发生的选择性退行性变化。这些 将测试经修饰的神经营养因子的中和能力 导致分子、形态和行为缺陷 实验性损伤。其他研究，使用免疫组织化学和 逆行运输方法，旨在确定以前未知的 神经营养因子反应细胞群。总而言之，这个程序 该项目旨在确定修饰的神经营养因子能够特异性地 影响退行性变神经元群体的生存和功能 阿尔茨海默氏症。希望这些研究将导致 限制性或加宽修饰神经营养因子的发现 生物特异性与它们的自然对应物和 在鉴定最有前途的分子方面 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。

Alzheimer's disease (AD) is associated with degenerative changes and loss of various populations of neurons in the brain. Since neurotrophic factors regulate neuronal survival and maintenance of function, such factors 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 under consideration as experimental treatment for AD. One specific aim of this application, related to NGF's long-term effects and the feasibility of slow-releasing implants, will provide additional information valuable for clinical use of NGF. However, the value of NGF in the treatment of AD is limited by its specificity for forebrain cholinergic neurons. The recent discovery of homologs of NGF, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), established the family of neurotrophins. These neurotrophins affect a variety of peripheral and central neurons and their effects overlap for some neuronal populations but differ for others. Recent findings, which provide the basis for this application, indicate that posttranslational modifications of the neurotrophins influence their biological activities and their specificity to act on subsets of neuronal populations. Therefore, it is proposed to prepare modified molecular forms of the neurotrophins either by recombinant expression or by specific protease treatment. Biological effects of these modified neurotrophins will then be characterized initially in neurotrophin receptor assays and in cell culture assays.Biologically active modified neurotrophins selected by the in vitro assays will then be tested in vivo in rat brain lesion models mimicking selective degenerative changes occurring in AD brains. These modified neurotrophins will be tested for their ability to counteract molecular, morphological, and behavioral deficits induced by the experimental lesions. Additional studies, using immunohistochemistry and retrograde transport methodologies, aim at identifying previously unknown neurotrophin-responsive cell populations. In summary, this program project aims at identifying modified neurotrophins able to specifically affect survival and function of neuronal populations degenerating in Alzheimer's disease. It is hoped that the studies will lead to the discovery of modified neurotrophins with either restricted or broadened biological specificity when compared with their natural counterparts and in the identification of molecules most promising 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.