Abstract
Diabetic depression increases in association with microvascular complications. We tested a hypothesis that circulating autoantibodies having anti-endothelial and anti-neuronal properties increase in subsets of diabetes with co-morbid depression. Protein-A eluates from plasma of 20 diabetic depression patients and 30 age-matched controls were tested for effects on endothelial cell survival, neurite outgrowth in rat pheochromocytoma (PC12) cells, or process extension and survival in adult rat dentate gyrus neural progenitor cells. The protein-A eluates from depressed or non-depressed, diabetic patients were injected (via intracerebroventricular route) into mice and 7-10 days later behavioral tests (sucrose preference, and tail suspension tests) were conducted to determine whether the autoantibodies induced anhedonia or despair. Diabetic depression (n=20) autoantibodies caused a significant inhibition of PC12 cell neurite outgrowth (P<0.001) or endothelial cell proliferation compared to autoantibodies in control, diabetic (n=20) or non-diabetic (n=10) patients without depression. Process extension and survival in adult rat dentate gyrus neural progenitor cells was significantly reduced (P<0.001) by diabetic depression autoantibodies (n= 11) compared to the effects from similar concentrations (5-7 μg/mL) of autoantibodies in diabetic (n=12) or non-diabetic patients without depression (n=7). Ten micromolar concentrations of Y27632, a selective Rho-Associated Protein Kinase (ROCK) inhibitor, significantly prevented (P<0.0001) neural progenitor cell process retraction induced by diabetes depression autoantibodies (n=5). Mice treated with diabetic depression autoantibodies (n=16 from two different patients' autoantibodies) exhibited significantly reduced (P=0.027) sucrose preference (anhedonia) compared to mice treated with diabetic control autoantibodies (n=16 from two different patients' autoantibodies). These data suggest that autoantibodies in a subset of older adult diabetic depression inhibit endothelial cell survival, and impair process extension and survival in adult dentate gyrus neural progenitor cells in vitro.
Highlights
Depression affects neurons in the prefrontal cortex and hippocampus [1] and depression increases among the millions of older adults affected by diabetes worldwide [2,3,4]
We examined plasma autoantibodies in 20 older adults with type 2 diabetic depression, and 30 age-matched (20 diabetic and 10 non-diabetic) non-depressed patients for effects on endothelial cell proliferation, neurite outgrowth in rat pheochromocytoma (PC12) cells, or process extension and survival in adult rat dentate gyrus neural progenitor cells
Protein-A eluates (30 μg/mL) in diabetic depression patients caused significant (P=0.014) inhibition of EC survival compared to the protein-A eluates in diabetes without depression [Figure 1]
Summary
Depression affects neurons in the prefrontal cortex and hippocampus [1] and depression increases among the millions of older adults affected by diabetes worldwide [2,3,4]. Unknown factors elaborated by injured glomerular capillary endothelial cells might play a causative role in subsets of diabetic depression. Fibroblast growth factor 2 increases in plasma in micro- or albuminuric diabetes [11] yet low plasma FGF2 levels occurred together with endothelial cell inhibitory autoantibodies in subsets of diabetic macular edema, and /or nephropathy [12,13]. Glomerular loss of HSPG occurs early in diabetic albuminuria [14] and since HSPG is a known target for autoimmunity [15], diabetic plasma autoantibodies which target the HSPG, FGF low affinity receptor may disrupt a broad spectrum of FGF2-mediated cellular effects [9] in neurons and endothelial cells
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