AUTHOR=Zimering Mark B., Moritz Thomas E., Donnelly Robert J.

TITLE=Anti-Neurotrophic Effects from Autoantibodies in Adult Diabetes Having Primary Open Angle Glaucoma or Dementia

JOURNAL=Frontiers in Endocrinology

VOLUME=4

YEAR=2013

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2013.00058

DOI=10.3389/fendo.2013.00058

ISSN=1664-2392

ABSTRACT=<p><bold>Aim:</bold> To test for anti-endothelial and anti-neurotrophic effects from autoantibodies in subsets of diabetes having open-angle glaucoma, dementia, or control subjects.</p><p><bold>Methods:</bold> Protein-A eluates from plasma of 20 diabetic subjects having glaucoma or suspects and 34 age-matched controls were tested for effects on neurite outgrowth in rat pheochromocytoma PC12 cells or endothelial cell survival. The mechanism of the diabetic glaucoma autoantibodies’ neurite-inhibitory effect was investigated in co-incubations with the selective Rho kinase inhibitor Y27632 or the sulfated proteoglycan synthesis inhibitor sodium chlorate. Stored protein-A eluates from certain diabetic glaucoma or dementia subjects which contained long-lasting, highly stable cell inhibitory substances were characterized using mass spectrometry and amino acid sequencing.</p><p><bold>Results:</bold> Diabetic primary open angle glaucoma (POAG) or suspects (<italic>n</italic> = 20) or diabetic dementia (<italic>n</italic> = 3) autoantibodies caused significantly greater mean inhibition of neurite outgrowth in PC12 cells (<italic>p</italic> &lt; 0.0001) compared to autoantibodies in control diabetic (<italic>n</italic> = 24) or non-diabetic (<italic>n</italic> = 10) subjects without glaucoma (<italic>p</italic> &lt; 0.01). Neurite inhibition by the diabetic glaucoma autoantibodies was completely abolished by 10 μM concentrations of Y27632 (<italic>n</italic> = 4). It was substantially reduced by 30 mM concentrations of sodium chlorate (<italic>n</italic> = 4). Peak, long-lasting activity survived storage ×5 years at 0–4°C and was associated with a restricted subtype of Ig kappa light chain. Diabetic glaucoma or dementia autoantibodies (<italic>n</italic> = 5) caused contraction and process retraction in quiescent cerebral cortical astrocytes effects which were blocked by 5 μM concentrations of Y27632.</p><p><bold>Conclusion:</bold> These data suggest that autoantibodies in subsets of adult diabetes having POAG (glaucoma suspects) and/or dementia inhibit neurite outgrowth and promote a reactive astrocyte morphology by a mechanism which may involve activation of the RhoA/p160 ROCK signaling pathway.</p>