Alzheimer's Disease Beta-Amyloid in the Lens

描述(由申请人提供)：这一新的由研究人员发起的申请是为NIA赞助的阿尔茨海默病指导科学家职业发展奖(K08)(RFA AG-02-006)。应聘者的申请是为了在他迈向独立学术研究生涯的过程中加强他的专业培训和跨学科研究经验。阿尔茨海默病(AD)的特征是大脑中主要由β-淀粉样多肽(Abeta)组成的蛋白质聚集体。这位候选人最近在人类晶状体中发现了Abeta，表明晶状体中AI3的组织浓度与大脑相当，并确定这种致病多肽作为新的胞浆聚集体聚集在晶状体纤维细胞中。这些与β相关的聚集体是电子密度和散射光的。此外，晶状体Abeta与核上型/皮质深部晶状体亚区的罕见白内障有关，这些晶状体亚区是在死后神经病理确诊的AD供体中发现的。候选人进行的生化研究表明，Abeta与其他胞浆晶状体蛋白相互作用，并通过金属蛋白氧化还原反应促进致病晶状体蛋白聚集。这种由Abeta介导的晶状体蛋白聚集可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存在与AD相关的重叠分子病理生理学。这些初步发现，如果得到证实，可能具有重要的临床诊断和治疗意义。候选人的研究计划将集中于对其初步发现的严格跟踪，将包括：1)系统地测定来自正常老年人、白内障、AD和唐氏综合症捐赠者的晶状体标本中AB多肽的表达和分布模式、超微结构定位和体内局部浓度；以及2)彻底表征Abeta对晶状体蛋白质聚集的生物化学和生物物理效应。这些研究的结果将阐明AB晶状体的病理生物学，AD中晶状体和脑病理之间的假定关系，以及这些新发现可能的诊断和治疗意义。这一研究和培训计划将为候选人提供坚实的基础，以便启动进一步的跨学科调查，并开始他专注于AD的独立学术研究生涯。

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.