ALZHEIMER'S DISEASE, PLASTIC NEURITES AND NEURON-GLIA INTERACTION

定量高尔基体和电子显微镜数据表明与年龄相关的 在正常衰老的人的区域中树突范围的增加， 猴子和大鼠的大脑也在失去神经元，这让我们 假设存活的神经元对 与年龄有关的邻居的死亡。更多证据表明 不存在这种与年龄相关的树突状范围的净增加 阿尔茨海默病(AD)，这导致我们假设 阿尔茨海默病大脑进行代偿反应的能力。我们建议 通过量化生长相关蛋白来检验这些假说， GAP-43及其异构体及其在正常衰老和AD人脑中的信息。 提供的初步数据表明AD中GAP-43存在缺陷 大脑。提出了一系列细胞间信令，其开始于 死亡神经元改变蛋白质表达--向神经胶质细胞传递信号-- 神经营养/毒性和轴突延长因子表达的改变 存活神经元的神经胶质细胞反应。我们假设IL-1β 是这个信号级联中的一个分子。我们还建议在 在这一级联中有一个病变(S)。给出了初步数据。 支持胶质细胞和树突状细胞之间的假设关系 这种关系在早发性阿尔茨海默病中失败。研究是 应该测试此模型的选定方面，以及 AD中的信令可能会失败。作为这些研究的一部分，我们建议量化 至少一种已知蛋白质IL-1β的水平及其在 衰老与阿尔茨海默病脑，以及在微外植体体外模型系统中 这些分子的来源。因为没有一种单一的隔离方法 适用于所有分子，我们建议强调多肽，因为信号 大脑中的分子通常是多肽(例如许多多肽递质 候选者、激素和营养分子)。我们建议使用反向 相高效液相色谱法，以及最近的修饰，以分离这些多肽。这是 选择多肽分离的方法因为多肽通常是 通过翻译后加工从较大的前体分子中切割出来的。 分离出的多肽将被筛选出模型提出的活性， 有趣的多肽将被测序。本课程将探索数据库 与所开发的序列进行任何匹配。抗病毒抗体和cDNAs探针 选定的多肽将被开发并用于测试是否存在 这些多肽及其在啮齿类动物脑中的信息与 神经元死亡，在正常衰老和阿尔茨海默病脑。不管是否 这些研究支持神经元生长的假说。 正常衰老的大脑中的过程和这种生长的相对失败 在AD大脑中，他们应该提供可靠的数据来评估这一点 假设。细胞间信号转导Will模型的研究 不管神经元生长的假说是否有用 进程仍然有效，因为它将提供有关 神经元死亡与胶质细胞增多症相关的机制，以及 神经营养/毒性和轴突延长因子的产生 胶质细胞，以及AD对这些过程的某些方面的影响。AS 因此，建议的研究将提供研究的另一个切入点 导致阿尔茨海默氏症的病理级联。

Quantitative Golgi and electron microscopic data suggest a net age-related increase in dendritic extent in regions of the normally aging human, monkey and rat brain that are also losing neurons, which leads us to hypothesize a plastic, compensatory response of surviving neurons to the age-related death of their neighbors. Additional evidence suggests absence of this net age-related increase in dendritic extent in Alzheimer's disease (AD), which leads us to hypothesize a decreased ability of the AD brain to mount a compensatory response. We propose to test these hypotheses by quantification of the growth-associated protein, GAP-43, its isoforms and its message in normally aging and AD human brain. Preliminary data are presented indicating deficiencies in GAP-43 in the AD brain. A cascade of intercellular signaling is proposed which starts with altered expression of proteins by dying neurons -> signals to glia -> altered expression of neurotrophic/toxic and neurite elongation factors by glia -> response of the surviving neurons. We hypothesize that IL-1beta is one of the molecules in this signal cascade. We also suggest that in AD there is a lesion(s) in this cascade. Preliminary data are presented that support the hypothesized relationship between glia and dendritic extent, and a failure of this relationship in early onset AD. Studies are supposed to test selected aspects of this model, as well as where the signaling may fail in AD. As part of these studies we propose to quantify levels of at least one known protein, IL-1beta, and its message in the aging and AD brain, as well as in a microexplant in vitro model system as a source of these molecules. Since no single method of isolation is suitable for all molecules we propose to emphasize peptides since signal molecules in the brain are often peptides (e.g. many peptide transmitter candidates, hormones and trophic molecules). We propose to use reverse phase HPLC, and recent modifications, to isolate these peptides. This is the method of choice for peptide isolation since peptides are usually cleaved from larger precursor molecules by posttranslational processing. Peptides isolated will be screened for activities proposed by the models, and interesting peptides will be sequenced. Data bases will be explored for any match with the sequences developed. Antibodies and cDNA probes to selected peptides will be developed and used to test for the presence of the these peptides and their messages in rodent brain in relation to neuron death and in normally aging and AD brain. Regardless of whether the studies proposed support the hypothesis of growth of neuronal processes in the normally aging brain and relative failure of this growth in the AD brain, they should provide solid data toward evaluating this hypothesis. Study of the proposed model of intercellular signaling will be useful regardless of whether the hypotheses of growth of neuronal processes remain tenable, for it will provide information concerning the mechanisms by which neuron death is associated with gliosis, as well as the production of neurotrophic/toxic and neurite elongation factors by glia, and the effects of AD on selected aspects of these processes. As such, the studies proposed will provide another entry point into study of the pathological cascade that results in Alzheimer's disease.