Abstract
Purpose: :
Alzheimer Aß pathology is mechanistically linked with diabetes and insulin resistance. Recently, we showed that neuronal and Alzheimer related vesicle transport proteins are extensively shared in the lens, and that basic transcriptional and post-transcriptional regulation that governs neurogenesis also uniquely occurs in lens. Here, we test the idea that as a result, coordinate Aß pathology occurs in lens and brain when we apply system-wide stress in the form of diabetes and hyperglycemia. We also developed a laser-based instrument to non-invasively detect and measure Aß biomarkers in the intact lens.
Methods: :
Brain and lens from rabbits rendered diabetic with alloxan for 16 wks were examined using in situ, ELISA and laser spectrometry Aß detection methods. Insulin receptor and Aß antibodies against monomeric and higher order Aß moietes were used.
Results: :
Widespread Aß pathology was detected with antibodies against monomeric and higher order Aß structures in brain, and lenses. Aß plaques were widespread in hippocampus and cortex and Aß in lenses accumulated primarily in the periphery. Separate quantitative ELISA assays detected >4-fold increase in Aß ending at amino acid 40 and ending at 42 in diabetic lens, hippocampus and cortex. Laser spectrometry measured ~4-fold increase in Aß in intact lenses, matching ELISA determinations.
Conclusions: :
Substantial Aß pathology was coordinately produced in brain and lens in wild-type diabetic rabbits after 16 weeks. Non-invasive laser spectrometry measurements of Aß biomarkers in lens matched levels determined in vitro with ELISA methods and agree with in situ results. Our 16 week "end-point" study provided strong evidence consistent with our hypothesis that corresponding Aß pathology and Aß accumulation coordinately occurs in brain and lenses, which can be detected and quantified spectrophotometrically in the lens. Future studies on the kinetics and relative onset at earlier time points after inducing diabetes and hyperglycemia will determine the ability to use Aß levels in tissue outside the brain "like a blood test" (or other fluids that have been proposed), and will determine the ability of our spectrometry instrumentation to provide useful diagnostic information about the onset and progression of Aß pathology in brain, beginning with models of shared systemic stress in diabetes.
Keywords: diabetes • pathobiology • cataract