NRG1 Isoform-10 ELISA Kit

Neuregulin-1 (NRG1) and ErbB receptors have been associated with psychopathology, and NRG1-ErbB3 signaling has been shown to increase hippocampal neurogenesis and induce antidepressant-like effects. In this study, we aimed to determine whether deficits in NRG1 or ErbBs might be present in the hippocampus of suicide completers. In well-characterized postmortem hippocampal samples from suicides and matched sudden-death controls, we assessed gene expression and methylation using qRT-PCR and EpiTYPER, respectively. Moreover, in hippocampal tissues stained with cresyl violet, stereology was used to quantify numbers of granule cells and of glia. Granule cell body size was examined with a nucleator probe, and granule cell layer volume with a Cavalieri probe. Unmedicated suicides showed sharply decreased hippocampal ErbB3 expression and decreased numbers of ErbB3-expressing granule cell neurons in the anterior dentate gyrus; a phenomenon seemingly reversed by antidepressant treatment. Furthermore, we found ErbB3 expression to be significantly decreased in the dentate gyrus of adult mice exposed to chronic social defeat stress. Taken together, these results reveal novel suicidal endophenotypes in the hippocampus, as well as a putative etiological mechanism underlying suicidality, and suggest that antidepressant or NRG1 treatment may reverse a potential deficit in anterior dentate gyrus granule cell neurons in individuals at risk of dying by suicide.

Neuregulin-1 (NRG1), known also as heregulin, acetylcholine receptor inducing activity (ARIA), glial growth factor (GGF), or sensory and motor neuron derived factor (SMDF), is a key factor for many developmental processes and in adult brain. All known splice variants contain an epidermal growth factor (EGF)-like domain, which is mediating signaling via receptors of the ErbB family. In particular, NRG1 acts as an essential signaling molecule expressed on the axonal surface, where it signals to Schwann cells throughout development and regulates the thickness of the myelin sheath. NRG1 is required also by other cell types in the nervous system, for instance as an axonal signal released by proprioceptive afferents to induce development of the muscle spindle, and it controls aspects of cortical interneuron development as well as the formation of thalamo-cortical projections. The precursor protein of NRG1 can be activated and released from the membrane through limited proteolysis by the beta-Secretase (beta-site amyloid precursor protein cleaving enzyme 1, BACE1) which was first identified through its function as the rate limiting enzyme of amyloid-beta-peptide (A beta) production. A beta is the major component of amyloid plaques in Alzheimer's disease (AD). Due to the hairpin nature of NRG1 type III two membrane-bound stubs with a type 1 and a type 2 orientation are generated by an initial proteolytic cleavage and successive release of the EGF-like domain either by dual cleavage by BACE1 or by ADAM17 (a disintegrin and metalloprotease) which is also called TACE (Tumor Necrosis Factor-alpha-converting enzyme). The cleavages activate NRG1 to allow juxtacrine or paracrine signaling. The type 1 oriented stub is further cleaved by gamma-secretase in the transmembrane domain with a putative role in intracellular domain (ICD) signaling, while the type II oriented stub is cleaved by signal peptidase like proteases (SPPLs). Neuregulin-1 was identified as a major physiological substrate of BACE1 during early postnatal development when similarities in BACE1 KO mice and NRG1 heterozygous mice were discovered. Both display severe hypomyelination of peripheral nerves. Later it was shown with genetic and pharmacological evidence that the developmental effect of type I NRG1 on the formation and the maintenance of muscle spindles is BACE1 dependent. Thus, NRG1 functions in PNS and CNS are likely to set limits to an Alzheimer disease therapy with relatively strong BACE1 inhibition. (C) 2016 Elsevier Inc. All rights reserved.