COMPUTER AIDED STUDY OF DENDRITES IN AGING HUMAN BRAIN

计算机辅助研究衰老人脑中的树突

• 批准号: 3114157
• 负责人: PAUL D COLEMAN
• 金额: $ 15.13万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-07-01 至 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3114157
• 关键词: Alzheimer's disease; aging; astrocytes; axon; brain cell; brain disorder diagnosis; brain disorders; cerebral cortex; computer assisted diagnosis; dendrites; glia; histopathology; human tissue; immunocytochemistry; neural degeneration; neural plasticity; neuroanatomy; neurogenesis; neuropil; postmortem; western blottings

Previous quantitative Golgi studies have demonstrated age-related increases in dendritic extent in normal old human and animal brain but not in AD brain. In model regions that do not lose neurons with aging such age-related increase in dendritic extent is not found. We interpret these data as suggesting that neurons in the normal brain can respond to the age-related death of their neighbors with a plastic proliferation of additional dendritic material, and that this capacity is altered in AD. Model mechanisms that may aid in understanding this normal age- related dendritic proliferation include those that emphasize a glial response (probably astrocytic) to neuron death as providing trophic factor(s), while other models emphasize reduced competition for afferent supply consequent to the death of neighboring, competing neurons as allowing dendritic proliferation of the surviving neurons. We present preliminary data from human neocortex that indicate a positive relationship between numbers of glia and the extent of the dendritic neuropil (average dendritic extent per single neuron times the number of neurons of that type) in normal aging human brain and in late onset AD, but apparent breakdown of this relationship in early onset (long duration) AD. In this proposal we outline plans to capitalize on recent discoveries in protein correlates of neuronal growth and plasticity and also on the ability to differentially stain glial subtypes in postmortem human brain to confirm and extend our preliminary studies of the relationship between glia and the neuropil to test five hypotheses: (1) that the positive relationship between glia and neurites that has been shown by the in vitro work of others extends to the postmortem human brain, (2) that this relationship is disturbed in early onset (and/or long duration?) AD, (3) that the relationship is attributable largely to astrocytes, (4) that this relationship can be confirmed and extended to include axons by relating numbers of glia to levels of the neuronal growth associated protein, GAP-43, in postmortem human brain, and (5) start to test the hypothesis that the relationship between glia and dendritic neuropil is a function of age-related neuron death rather than being established during early development by dissecting the components of the dendritic tree into the early formed primary dendrites and the more recently formed terminal dendritic segments and examining the relationship of glia to the extent of each of these portions of the dendritic tree. These studies will also allow us to extend our hypotheses that there is residual neuronal plasticity in the normal aged human brain and that AD may be accompanied by diminished neuronal plasticity by using GAP-43 as an alternate measure of neuronal growth and plasticity.

先前的定量高尔基体研究已证明与年龄相关 正常老年人和动物大脑的树突状程度增加 但在 AD 大脑中则不然。 在不丢失神经元的模型区域 随着年龄的增长，这种与年龄相关的树突程度的增加并不 成立。 我们将这些数据解释为表明 正常的大脑可以对与年龄相关的死亡做出反应 具有额外树突的塑料增殖的邻居 材料，并且这种能力在AD中被改变。 可能有助于理解这种正常年龄的模型机制 相关的树突增殖包括那些强调 神经胶质细胞对神经元死亡的反应（可能是星形细胞） 营养因子，而其他模型则强调减少竞争 对于邻居死亡造成的传入供应， 竞争性神经元允许树突增殖 幸存的神经元。 我们提供来自人类的初步数据 新皮质表明数量之间存在正相关关系 神经胶质细胞和树突状神经纤维的范围（平均树突状神经纤维） 每个单个神经元的范围乘以该类型神经元的数量） 在正常老化的人类大脑和迟发性 AD 中，但明显 这种关系在早期（长期）AD 中被破坏。 在本提案中，我们概述了利用最近的计划 与神经元生长和可塑性相关的蛋白质的发现 以及对神经胶质亚型进行差异染色的能力 尸检人脑以确认并扩展我们的初步研究 研究神经胶质细胞和神经纤维之间的关系以测试 五个假设：（1）神经胶质细胞之间的正相关关系 和其他人的体外工作显示的神经突 延伸到死后的人类大脑，（2）这种关系 在早期发作（和/或长期持续？）AD 中受到干扰，(3) 这种关系主要归因于星形胶质细胞，(4) 这种关系可以得到确认并扩展到包括轴突 通过将神经胶质细胞的数量与神经元生长的水平联系起来 死后人脑中的相关蛋白 GAP-43，以及 (5) 开始检验神经胶质细胞和神经胶质细胞之间关系的假设 树突状神经元是与年龄相关的神经元死亡的功能，而不是 而不是在早期开发过程中通过剖析来建立 树突树的组成部分进入早期形成的初级 树突和最近形成的末端树突片段 并检查神经胶质细胞与每个范围的关系 树突树的这些部分。 这些研究还将使我们能够扩展我们的假设 正常老年人中存在残余的神经元可塑性 AD 可能伴随着神经元减少 使用 GAP-43 作为神经元的替代测量方法来评估可塑性 生长和可塑性。