The candidate for this award is a clinician-scientist with a strong focus on interdisciplinary translational research in Alzheimer's disease (AD) and cataracts. These chronic degenerative disorders of aging involve pathogenic protein aggregation and are leading contributors to morbidity/mortality in the elderly. AD is characterized by cerebral accumulation of beta-amyloid (Abeta) peptides. We have recently identified Abeta deposition, amyloid pathology, and co-localizing supranuclear cataracts in lenses from AD but not non- AD patients. Both Abeta 1-40/42 isoforms were sequenced from lens and aqueous humor at concentrations comparable to brain and cerebrospinal fluid, respectively. Abeta collects in lens fiber cells as cytosolic aggregates that scatter light. Abeta enrichment in AD lenses demonstrated classical amyloid tinctorial properties in the equatorial supranucleus. Abeta potentiated lens protein aggregation via metalloprotein redox reactions is blocked by chelation or antioxidants. Abeta binds alphaB-crystallin, a cytosolic lens protein and heat shock protein/molecular chaperone upregulated in AD brains. Abeta and alphaB-crystallin co-immunopurify from AD lens/brain. Taken together, these data suggest possible overlapping molecular pathophysiology in AD brain and lens. In light of this progress, this application details programmatic expansion and acceleration of the candidate's recent Alzheimer's disease career development (K08) award. The present proposal details intensive career development programming with directed interdisciplinary research mentorship, focused specialty technical training, and critical support to enhance the candidate's ability to specifically address the scientific questions raised by these discoveries. The candidate will: i) determine Abeta expression/distribution patterns, ultrastructural localization, and regional Abeta concentration in lenses and brain from aged, cataractous, AD, and non-AD control donors; ii) characterize the biochemistry/biophysics of Abeta-mediated effects on lens protein aggregation, chaperone function, and peroxide production. These studies will validate the present data set, clarify the relationship between brain and lens AD pathology, and provide detailed mechanistic insight into amyloid formation and cataractogenesis. Study results may yield novel diagnostic/therapeutic strategies for AD and cataracts. This career development program will provide a strong foundation from which the candidate will initiate future interdisciplinary investigations and launch an independent academic research career in aging.
| Moncaster, Juliet A; Pineda, Roberto; Moir, Robert D et al. (2010) Alzheimer's disease amyloid-beta links lens and brain pathology in Down syndrome. PLoS One 5:e10659 |
