Radical generation and propagation in biological systems

阿尔茨海默氏病（AD）是一种破坏性的老年神经元病症，其折磨10%的65岁以上的人口。 它是无法治愈的，通常在痛苦的退化期后10年内死亡。 它是由神经细胞的死亡引起的，主要是由单个小肽（42个残基）的作用引起的，淀粉样β肽（Abeta）以聚集的形式，最有可能与结合的氧化还原活性铜结合。 Abeta对神经元的攻击是多管齐下的。 具有氧化还原活性的铜产生超氧化物和过氧化氢，并通过引发脂质过氧化来破坏膜。 低聚物形式通过多种机制具有毒性。一段时间以来，我们一直在应用复杂的计算机建模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的化学性质及其与金属铜的关系的许多方面。经过两年的计算机模拟，我们有了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组装成寡聚体，我们已经花费了相当大的努力来设计将特异性结合单体Abeta的化合物。我们已经设计了几个候选药物家族，并合成和测试了其中两种药物预防寡聚化的能力，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，通过计算研究肽-肽相互作用的热力学，重点是我们的候选药物和Abeta的靶向片段。 我们还建议检查由二十二碳六烯酸组成的膜的结构，二十二碳六烯酸是一种在大脑中非常常见的多不饱和脂肪酸，它对小物种如NO，O2，CO和H2 O2的渗透性，以及对Abeta的亲和力。 我们还建议研究Abeta与结合铜的小聚集体，以确定其导致大脑血液供应受限的能力，以证实我们发表的缺席假设中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.