Anti-neurotrophic effects from autoantibodies in adult diabetes having primary open angle glaucoma or dementia

Mark B Zimering, Thomas E Moritz, Robert J Donnelly, Mark B Zimering, Thomas E Moritz, Robert J Donnelly

Abstract

Aim: To test for anti-endothelial and anti-neurotrophic effects from autoantibodies in subsets of diabetes having open-angle glaucoma, dementia, or control subjects.

Methods: 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.

Results: Diabetic primary open angle glaucoma (POAG) or suspects (n = 20) or diabetic dementia (n = 3) autoantibodies caused significantly greater mean inhibition of neurite outgrowth in PC12 cells (p < 0.0001) compared to autoantibodies in control diabetic (n = 24) or non-diabetic (n = 10) subjects without glaucoma (p < 0.01). Neurite inhibition by the diabetic glaucoma autoantibodies was completely abolished by 10 μM concentrations of Y27632 (n = 4). It was substantially reduced by 30 mM concentrations of sodium chlorate (n = 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 (n = 5) caused contraction and process retraction in quiescent cerebral cortical astrocytes effects which were blocked by 5 μM concentrations of Y27632.

Conclusion: 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.

Keywords: autoantibodies; dementia; diabetes mellitus; neurite outgrowth; open angle glaucoma.

Figures

Figure 1
Figure 1
Diabetic glaucomatous autoantibodies inhibit neurite expression in PC 12 cells (A) highest neurite-inhibitory activity was associated with glaucomatous vision loss (B) and was eliminated by treatment with Y27632 (C) or 30 mM sodium chlorate (D). (A-D) Thirty microgram per milliliter concentrations of the protein-A eluate fraction of plasma was incubated with PC12 cells in the presence or absence of 10 μM concentrations of Y27632 (C) or 30 mM concentrations of sodium chlorate (D) as described in Section “Materials and Methods.” Results (mean ± 1 SD of four different protein-A eluates) are expressed as % neurite expression compared to cells incubated with 10 ng/mL concentrations of basic fibroblast growth factor alone [i.e., 100%, open bars (C,D)]. DM, diabetes mellitus; Glc, glaucoma or suspect (susp); Dmt, dementia; VF, visual field.
Figure 2
Figure 2
Effect of diabetic glaucomatous autoantibodies on astrocyte morphology. Morphology in cerebral cortical astrocytes (A) before or (B) 30 min after addition of 10 μg/mL concentration of protein-A eluate from type 2 DM and glaucoma; (C) before or (D) 10 min after addition of 3 μg/mL concentration of the protein-A eluate fraction from type 2 DM having glaucoma and Alzheimer’s type dementia (Pt 1). Antibodies caused varying degrees of withdrawal of thick astrocyte processes associated with increased stress fiber expression (arrows), and cell contraction (vertical lines). Astrocytes cultured in the presence of 10 μM concentrations of Y27632 for 10 min before (E) and after (F) addition of a 3 μg/mL concentration of the Pt 1 protein-A eluate fraction did not undergo similar changes in their appearance. Results similar to those shown in (A–D) were obtained in eight experiments using 3–10 μg/mL concentrations of autoantibodies from five different diabetic glaucoma patients. Much less if any acute change in morphology was observed (n = 4 experiments) using 10–20 μg/mL concentrations of protein-A eluate from four type 2 DM subjects without glaucoma.

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