Inhibitors of Alzheimer's Disease Amyloidosis

描述(申请人提供)：阿尔茨海默病(AD)是一种退行性疾病 以记忆力进行性丧失为临床特征的脑部疾病， 认知、推理、判断和情绪稳定，逐渐导致 严重的精神恶化，最终导致死亡。广告是最主要的原因 老年人中的痴呆症，今天影响到400万到500万美国人，这是 预计在未来25年内发病率将翻一番。广告的特点是 脑内不溶纤维淀粉样沉淀物的积聚 β-淀粉样蛋白(ABeta)，无论是作为细胞外淀粉样斑块在 脑实质或血管壁内。AB淀粉样蛋白的形成、沉积和 脑中的持续性被认为在AD的发病机制中起着核心作用 导致神经元丧失和记忆功能障碍，因此成为 开发治疗AD和AD的新药的中心目标 发病年限。 我们的I期SBIR研究表明，基底膜蛋白 层粘连蛋白在体外和体内都是AB纤维形成的有效抑制因子。 活着。经弹性酶消化和测序后，在 层粘连蛋白定位于层粘连蛋白的C-末端球状结构域重复序列 Al链，在55 kDa的区域内。进一步鉴定了一个由12个氨基酸组成的多肽 在层粘连蛋白A1的第4球状结构域内成为ABeta的有效抑制剂 纤维形成。在筛选出300多个重叠的12-14个氨基酸之后 我们鉴定了不同层粘连蛋白α链球状结构域的酸性多肽 发现了六个理想的候选多肽(每个长度为12-13个氨基酸) 是ABeta淀粉样原纤维形成的有效抑制剂，并导致 预先形成的阿尔茨海默病淀粉样纤维断裂。基于这些有希望的结果， 第二阶段SBIR研究将涉及相关多肽类似物的合成 (即D-氨基酸，较小的截短肽)源自六个亲本 形成层粘连蛋白球状结构域衍生的多肽，目标是优化新的 具有1)抑制所有原纤维形成和 破坏/分解预制的ALL纤维，2)抑制ALL诱导的毒性，3) 抵抗快速的生物降解，4)穿过血脑屏障，5)延缓 或者逆转AD转基因小鼠模型中类AD淀粉样斑块的病理。 这些研究有望导致一种新的多肽的鉴定 治疗阿尔茨海默病及相关疾病中所有淀粉样变性的候选药物。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is the leading cause of dementia in the elderly, today affecting 4-5 million American, which is expected to double in incidence in the next 25 years. AD is characterized by the brain accumulation of insoluble fibrillar amyloid deposits containing the beta-amyloid protein (ABeta), either as extracellular amyloid plaques in the brain parenchyma or in blood vessel walls. AB amyloid formation, deposition and persistence in brain is believed to play a central role in AD pathogenesis by contributing to neuronal loss and memory dysfunction, and therefore has become a central target for the development of new drugs for the treatment of AD and years of disease onset. Our Phase I SBIR studies demonstrated that the basement membrane protein laminin acts as a potent inhibitor of AB fibril formation, both in vitro and in vivo. Following elastase digestion and sequencing, an AB-binding site on laminin was localized to the C-terminal globular domain repeats on the laminin Al chain, within a 55-kDa region. A 12 amino acid peptide was futher identified within the 4th globular domain of laminin Al to be a potent inhibitor of ABeta fibrillogenesis. Following the screening of over 300 overlapping 12-14 amino acid peptides of various laminin alpha-chain globular domains, we identified six ideal peptide candidates (each 12-13 amino acids in length) that were found to be potent inhibitors of ABeta amyloid fibril formation, and which cause a disruption of pre-formed AD amyloid fibrils. Based on these promising results, Phase II SBIR studies will involve the synthesis of related peptide analogs (i.e. D-amino acids, smaller truncated peptides) derived from the six parent form laminin globular domain-derived peptides with the goal of optimizing new peptides that have the ability to 1) inhibit All fibril formation and disrupt/disassemble preformed All fibrils, 2) inhibit All-induced toxicity, 3) resist rapid bio-degradation, 4) cross the blood-brain barrier, and 5) retard or reverse AD-like amyloid plaque pathology in a transgenic mouse model of AD. These studies are anticipated to lead to the identification of a new peptide candidate for the treatment of All amyloidosis in AD and related disorders.