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.
