COMPUTER AIDED STUDY OF DENDRITES IN AGING HUMAN BRAIN

以前的定量高尔基研究表明，与年龄有关 正常老年人和动物脑内树突范围的增加 但不是在AD的大脑中。在没有丢失神经元的模型区域中 随着年龄的增长，这种与年龄相关的树突范围并没有增加 找到了。我们将这些数据解读为表明大脑中的神经元 正常的大脑可以对与年龄相关的死亡做出反应 具有塑性扩散的邻居额外的树枝晶 材料，这一能力在公元后被改变。 可能有助于理解这个正常年龄的模型机制- 相关的树突状细胞增殖包括那些强调 神经胶质细胞对神经元死亡的反应(可能是星形胶质细胞) 营养因素(S)，而其他模型强调减少竞争 对于因邻居死亡而导致的传入补给， 相互竞争的神经元允许树突状细胞增殖 幸存的神经元。我们给出了来自人类的初步数据 新大脑皮层，表明 神经胶质细胞和树突神经束的范围(平均树突 每个单个神经元的扩展乘以该类型的神经元的数量) 在正常衰老的人脑和晚发性AD中，但明显 这种关系在早期(长病程)AD中的崩溃。 在这项提案中，我们概述了利用最近的 发现与神经元生长和可塑性相关的蛋白质 以及区分神经胶质细胞亚型的能力。 尸检人脑证实并延长了我们的初步 神经胶质细胞与神经纤维相互关系的研究 五个假设：(1)胶质细胞之间的正相关 和神经突起，这已经被其他人的体外研究所证明 延伸到死后的人脑，(2)这种关系 发病早(和/或持续时间长？)广告，(3) 这种关系主要归因于星形胶质细胞，(4) 这种关系可以被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) 开始检验一种假设，即胶质细胞和 树突状神经丛是年龄相关神经元死亡的一种功能 而不是在早期开发期间通过解剖 将树枝状树的成分转化为早期形成的初级 树枝和最近形成的末端树枝状节段 并检查神经胶质细胞之间的关系 树枝状树的这些部分。 这些研究还将使我们能够扩展我们的假设 正常老年人存在残存的神经元可塑性 脑和阿尔茨海默病可能伴有神经元减少 GAP-43作为神经元可塑性的替代指标 生长和可塑性。

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.