Alzheimer's Disease Beta-Amyloid in the Lens

阿尔茨海默病晶状体中的β-淀粉样蛋白

• 批准号: 6619323
• 负责人: LEE E. GOLDSTEIN
• 金额: $ 16.2万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6619323
• 关键词: Alzheimer's disease; Downs syndrome; aging; aminoacid; amyloid proteins; biomarker; cataract; clinical research; electron microscopy; fiber cell; free radical oxygen; human tissue; immunocytochemistry; immunoprecipitation; in situ hybridization; lens; lens proteins; light scattering; mass spectrometry; metalloproteins; molecular pathology; protein localization; protein sequence; western blottings

DESCRIPTION (provided by applicant): This new investigator-initiated application is for the NIA-sponsored Alzheimer's Disease Mentored Scientist Career Development (K08) Award (RFA AG-02-006). The candidate's application is designed to enhance his specialty training and interdisciplinary research experience as he progresses towards an independent academic research career. Alzheimer's disease (AD) is characterized by cerebral accumulation of protein aggregates composed predominantly of beta-amyloid (Abeta) peptides. The candidate has recently identified Abeta in the human lens, shown that the tissue concentration of AI3 in the lens is comparable to brain, and determined that this pathogenic peptide collects as novel cytosolic aggregates within lens fiber cells. These beta-associated aggregates are electron dense and scatter light. Moreover, lens Abeta is associated with an unusual cataract in the supranuclear/deep cortical lens subregions identified in postmortem donors with neuropathologically confirmed AD. Biochemical studies conducted by the candidate demonstrated that Abeta interacts with other cytosolic lens proteins and promotes pathogenic lens protein aggregation via metalloprotein redox reactions. This Abeta-mediated lens protein aggregation is completely blocked by metal chelators or antioxidant scavengers. Taken together, these data suggest possible overlapping AD-associated molecular pathophysiology in both the lens and the brain. These preliminary findings, if confirmed, may have clinically significant diagnostic and therapeutic implications. The candidate's research program will focus on rigorous follow-up of his preliminary discoveries and will include: 1) systematic determination of the expression and distribution patterns, ultrastructural localization, and regional in vivo concentrations of AB peptides in human lens specimens from normal aged, cataractous, AD, and Down's syndrome donors; and 2) thorough characterization of the biochemistry and biophysical effects of Abeta on lens protein aggregation. Results from these studies will clarify the pathobiology of lens AB, the putative relationship between lenticular and cerebral pathology in AD, and the possible diagnostic and therapeutic implications of these novel findings. This research and training program will provide the candidate with a firm foundation from which to initiate further interdisciplinary investigations and launch his independent academic research career focusing on AD.

描述（由申请人提供）：这项新的研究者发起的申请是针对NIA赞助的阿尔茨海默氏病指导的科学家职业发展（K08）奖（RFA AG-02-006）。 候选人的申请旨在增强他的专业培训和跨学科研究经验，因为他迈向了独立的学术研究职业。 阿尔茨海默氏病（AD）的特征是蛋白质聚集体的脑积累主要由β-淀粉样蛋白（ABETA）肽组成。 该候选者最近在人镜中鉴定出ABETA，表明晶状体中AI3的组织浓度与大脑相当，并确定该致病肽作为透镜纤维细胞中的新型胞质聚集体收集。 这些与β相关的聚集体是电子致密和散射光。 此外，镜头Abeta与在具有神经病理学确认的AD的验尸供体中鉴定出的牙本质/深层皮质晶状体子区域中的异常白内障有关。 候选人进行的生化研究表明，Abeta与其他胞质透镜蛋白相互作用，并通过金属蛋白氧化还原反应促进致病性透镜蛋白聚集。 这种Abeta介导的透镜蛋白聚集被金属螯合剂或抗氧化剂清除剂完全阻断。 综上所述，这些数据表明晶状体和大脑中可能重叠的AD相关分子病理生理。 这些初步发现（如果得到证实）可能具有临床上显着的诊断和治疗意义。 候选人的研究计划将重点关注其初步发现的严格随访，其中包括：1）在正常年龄，白内障，AD和Down的综合症供体的人类镜头标本中，有系统地确定表达和分布模式，超微结构定位以及AB肽的体内AB肽的区域浓度； 2）彻底表征Abeta对晶状体蛋白聚集的生物化学和生物物理作用。 这些研究的结果将阐明透镜AB的病理生物学，AD中的凸耳和脑病理学之间的假定关系以及这些新发现的诊断和治疗意义。 该研究和培训计划将为候选人提供牢固的基础，从中启动进一步的跨学科调查，并启动他的独立学术研究生涯，重点是广告。