Our work has demonstrated that fundamental neuron-specific cell biology processes that are focused on the Alzheimer beta-amyloid precursor protein (AbetaPP) are shared in the lens to a striking degree, and provided evidence that Abeta pathology is a key element in cataract formation similar to Alzheimer's disease (AD). Further, studies from our lab and recently others indicate that Abeta pathology in age-related cataract has a remarkably close association with corresponding changes in Abeta pathology in the brain in AD patients, and in animal models. These associations are consistent with an extensively shared biological diathesis for stress during aging in lens and brain and were indicated by our original studies. Now we will investigate the production of specific forms of Abeta pathology in the lens during early disease stages of cataract formation, and will also characterize its relationship with the onset and development of corresponding changes in Abeta pathology in brain. Specifically, we will characterize novel lens Abeta biomarkers we recently identified in the lens and explore their use for the early diagnosis of cataract, and investigate the use of these biomarkers for monitoring associated changes occurring in brain. Our second major goal is also to work to develop our recent novel application of sensitive laser-based technology to detect these Abeta biomarkers in the lens for the diagnosis of early stages of cataract, and will determine its ability to inform about related changes in the brain. This instrument is already providing us with a critical new research tool to help us understand the role of AD pathology in cataracts and relationship with brain. This work has already led to an understanding that 'workhorse'models in AD research also provide important models of age-related cataract. Our goal is to rigorously characterize Abeta biomarker increases in lens to understand their role in early cataractogenesis in human lens and our animal model, and to investigate onset of production in lens with onset of corresponding pathology in brain. This strictly non-invasive technology has significant potential to detect early stages of cataract prior to formation of significant light scattering or protein aggregation that presently are hallmarks of cataract diagnosis and efforts to monitor changes in brain. These studies build on our earlier studies to understand the role of AbetaPP and Abeta in the lens which are already providing a new and specific conceptual basis for understanding cataract and its links with the brain.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015855-04
Application #
7766214
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Araj, Houmam H
Project Start
2007-04-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$269,033
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Pharmacology
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
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Bitel, Claudine L; Kasinathan, Chinnaswamy; Kaswala, Rajesh H et al. (2012) Amyloid-ýý and tau pathology of Alzheimer's disease induced by diabetes in a rabbit animal model. J Alzheimers Dis 32:291-305
Frederikse, Peter H; Kasinathan, Chinnaswamy; Kleiman, Norman J (2012) Parallels between neuron and lens fiber cell structure and molecular regulatory networks. Dev Biol 368:255-60
Bitel, Claudine L; Singh, Vir; Frederikse, Peter H (2012) miR-124, miR-125b, let-7 and vesicle transport proteins in squid lenses in L. pealei. Curr Eye Res 37:388-94
Farooq, Mohammed; Kaswala, Rajesh H; Kleiman, Norman J et al. (2012) GluA2 AMPA glutamate receptor subunit exhibits codon 607 Q/R RNA editing in the lens. Biochem Biophys Res Commun 418:273-7
Bitel, Claudine L; Nathan, Rachel; Wong, Patrick et al. (2011) Evidence that "brain-specific" FOX-1, FOX-2, and nPTB alternatively spliced isoforms are produced in the lens. Curr Eye Res 36:321-7
Bitel, Claudine L; Perrone-Bizzozero, Nora I; Frederikse, Peter H (2010) HuB/C/D, nPTB, REST4, and miR-124 regulators of neuronal cell identity are also utilized in the lens. Mol Vis 16:2301-16