Radical generation and propagation in biological systems

阿尔茨海默病(AD)是一种破坏性的老年神经元疾病，在65岁以上的人口中有10%的人患有这种疾病。它是不治之症，通常在经历一段痛苦的退化期后10年内死亡。它是由神经细胞死亡引起的，主要是由单一小肽(42个残基)的作用引起的，即聚集形式的淀粉样β蛋白(Abeta)，最可能与结合的、氧化还原活性的铜结合。阿贝塔对神经元的攻击是多管齐下的。氧化还原活性铜产生超氧化物和过氧化氢，并通过引发脂质过氧化破坏细胞膜。低聚物通过多种机制是有毒的。一段时间以来，我们一直在应用复杂的计算机模型来研究在生理相关条件下所涉及的物种的基本化学。我们已经研究了Abeta化学的许多方面，以及它与金属铜的关联。经过两年的计算机模拟，我们有了一个Abeta本身的结构。我们和其他人认为，导致神经元死亡的复杂事件链中的薄弱环节是Abeta组装成低聚物，我们已经花费了相当大的努力来设计能够与单体Abeta特异结合的化合物。我们已经设计了几个候选药物家族，并合成并测试了其中两个家族的能力，以防止寡聚，并可能预防或至少减缓阿尔茨海默病的进展。本提案继续我们的AD化学研究，通过计算检查多肽-多肽相互作用的热力学，重点是我们的候选药物和Abeta的目标片段。我们还建议研究由二十二碳六烯酸组成的膜的结构，它是一种在大脑中非常常见的多不饱和脂肪酸，它对NO、O2、CO和H2O2等小分子的通透性，以及它对Abeta的亲和力。我们还建议研究结合铜的Abeta小聚集体，以确定它们导致大脑血液供应受限的能力，以证实我们发表的作为缺失假说的AD和血管性痴呆之间的假设联系。

Alzheimer's disease (AD) is a devastating neuronal condition of old age that afflicts 10% of the population over the age of 65. It is incurable and results in death usually within 10 years after a painful period of degeneration. It is brought about by the death of nerve cells caused largely by the action of a single small peptide (42-residues), the amyloid beta peptide (Abeta) in aggregated form, most likely with bound, redox active, copper. Abeta's assault on neurons is multipronged. The redox-active copper generates superoxide and hydrogen peroxide, and destroys membranes by initiating lipid peroxidation. The oligomeric form is toxic via a wide variety of mechanisms. For some time we have been applying sophisticated computer modeling to study the fundamental chemistry of the species involved under physiologically relevant conditions. We have examined many aspects of the chemistry of Abeta and its association with the metal, copper. After two years of computer simulation, we have a structure of Abeta itself. We and others believe that the weak link in the complex chain of events leading to neuronal death is the assembly of Abeta into oligomers, and we have expended considerable effort into the design of compounds that will bind specifically to monomeric Abeta. We have designed several families of drug-candidates, and synthesized and tested two of them for their ability to prevent oligomerization and possibly prevent, or at least slow down the progression of, Alzheimer's disease. The present proposal continues our AD chemistry investigation by examining computationally the thermodynamics of peptide-peptide interactions focusing on our drug candidates and targeted segments of Abeta. We also propose to examine the structure of a membrane composed of docosahexaenoic acid, a polyunsaturated fatty acid that is very common in in the brain, its permeability to small species like NO, O2, CO, and H2O2, and its affinity for Abeta. We also propose to study small aggregates of Abeta with bound copper to ascertain their ability to cause restriction of the blood supply to the brain, in order to confirm the hypothesized connection between AD and vascular dementia that we published as the ABSENT hypothesis.