Human Anti-Human PLXNB1 monoclonal Antibody, clone SFB839 [APC]

Background: Brain proteins, including Insulin-like Growth Factor Binding Protein 5 (IGFBP-5), have been associated with cognitive dysfunction in aging. Mechanisms linking depression with cognition are poorly understood. We hypothesize that the association of depressive symptoms with cognition is mediated or modified by brain proteins. Methods: IGFBP-5, HSPB2, AK4, ITPK1 and PLXNB1 were measured in dorsolateral prefrontal cortex in 1057 deceased participants, who underwent annual assessments of depressive symptoms and cognition for a mean of 8.9 years. The average number of depressive symptoms per year before a dementia diagnosis was calculated for each person. Results: A one standard deviation above the mean IGFBP-5 was associated with a 14% higher odds of having more depressive symptoms (p < 0.031). Higher IGFBP-5 was associated with faster decline in global cognition (p < 0.001) and five cognitive domains (p < 0.008), controlling for depressive symptoms. IGFBP-5 moderated the association of depressive symptoms with decline in global cognition (p= 0.045). IGFBP-5 mediated ten percent or less of the total effect of depressive symptoms on decline in global cognition and the cognitive domains (p > 0.070). Limitations: Participants were volunteers and self-selection bias limits the generalizability of our findings. In addition, we used self-reported data on depressive symptoms. However, we also used data on depression medications as sensitivity analyses to confirm findings. Conclusions: In old age, brain IGFBP-5 is associated with depressive symptoms and cognition. The association of depressive symptoms with cognitive decline is conditional on IGFBP-5.

Semaphorins, originally identified as axon guidance molecules, have also been implicated in angiogenesis, function of the immune system and cancerous growth. Here we show that deletion of Plexin B2 (Plxnb2), a semaphorin receptor that is expressed both in the pretubular aggregates and the ureteric epithelium in the developing kidney, results in renal hypoplasia and occasional double ureters. The rate of cell proliferation in the ureteric epithelium and consequently the number of ureteric tips are reduced in the kidneys lacking Plexin B2 (Plxnb2-/-). Semaphorin 4C, a ligand for Plexin B2, stimulates branching of the ureteric epithelium in wild type and Plxnb2+/- kidney explants, but not in Plxnb2-/- explants. As shown by co-immunoprecipitation Plexin B2 interacts with the Ret receptor tyrosine kinase, the receptor of Glial-cell-line-derived neurotrophic factor (Gdnf), in embryonic kidneys. Isolated Plxnb2-/- ureteric buds fail to respond to Gdnf by branching, but this response is rescued by Fibroblast growth factor 7 and Follistatin as well as by the metanephric mesenchyme. The differentiation of the nephrogenic mesenchyme, its morphology and the rate of apoptosis in the Plxnb2-/- kidneys are normal. Plexin B2 is co-expressed with Plexin B1 (Plxnb1) in the kidney. The double homozygous Plxnb1-Plxnb2-deficient mice show high embryonic lethality prior to onset of nephrogenesis. The only double homozygous embryo surviving to E12 showed hypoplastic kidneys with ureteric branches and differentiating mesenchyme. Taken together, our results show that Sema4C-Plexin B2 signalling regulates ureteric branching, possibly through modulation of Gdnf signalling by interaction with Ret, and suggest non-redundant roles for Plexin B1 and Plexin B2 in kidney development. (C) 2010 International Society of Differentiation. Published by Elsevier Ltd. All rights reserved.