Alzheimer's disease (AD) is associated with an altered immune response, resulting in chronic increased inflammatory cytokine production with a prominent role of TNF-α. TNF-α signals are mediated by two receptors: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Signaling through TNFR2 is associated with neuroprotection, whereas signaling through TNFR1 is generally proinflammatory and proapoptotic. Here, we have identified a TNF-α-induced proinflammatory agent, lipocalin 2 (Lcn2) via gene array in murine primary cortical neurons. Further investigation showed that Lcn2 protein production and secretion were activated solely upon TNFR1 stimulation when primary murine neurons, astrocytes, and microglia were treated with TNFR1 and TNFR2 agonistic antibodies. Lcn2 was found to be significantly decreased in CSF of human patients with mild cognitive impairment and AD and increased in brain regions associated with AD pathology in human postmortem brain tissue. Mechanistic studies in cultures of primary cortical neurons showed that Lcn2 sensitizes nerve cells to β-amyloid toxicity. Moreover, Lcn2 silences a TNFR2-mediated protective neuronal signaling cascade in neurons, pivotal for TNF-α-mediated neuroprotection. The present study introduces Lcn2 as a molecular actor in neuroinflammation in early clinical stages of AD.

Selenoproteins contain the essential trace element selenium, the deficiency of which is associated with cancer or accelerated aging. Although selenoproteins are thought to be instrumental for the effects of selenium, the biological function of many of these proteins remains unknown. Here, we studied the role of selenoprotein T (SelT), a selenocysteine (Sec) -containing protein with no known function, which we have identified as a novel target gene of the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) during PC12 cell differentiation. SelT was found to be ubiquitously expressed throughout embryonic development and in adulthood in rat. Immunocytochemical analysis revealed that SelT is mainly localized to the endoplasmic reticulum through a hydrophobic domain. PACAP and cAMP induced a rapid and long-lasting increase in SelT gene expression in PC12 cells, in a Ca(2+)-dependent manner. These results suggested a possible role of SelT in PACAP signaling during PC12 cell differentiation. Indeed, overexpression of SelT in PC12 cells provoked an increase in the concentration of intracellular Ca(2+) ([Ca(2+)](i)) that was dependent on the Sec residue. Conversely, SelT gene knockdown inhibited the PACAP-induced increase in [Ca(2+)](i) and reduced hormone secretion. These findings demonstrate the implication of a selenoprotein in the regulation of Ca(2+) homeostasis and neuroendocrine secretion in response to a cAMP-stimulating trophic factor.

The neuropeptide PACAP is an informational molecule released from stress-transducing neurons. It exerts post-synaptic effects required to complete hypothalamo-pituitary-adrenocortical (HPA) and hypothalamo-splanchnico-adrenomedullary (HSA) circuits activated by psychogenic and metabolic stressors. PACAP-responsive (in cell culture models) and PACAP-dependent (in vivo) transcriptomic responses in the adrenal gland, hypothalamus, and pituitary upon activation of these circuits have been identified. Gene products produced in response circuits during stress include additional neuropeptides and neurotransmitter biosynthetic enzymes and neuroprotective factors. Major portions of HPA and HSA stress responses are abolished in PACAP-deficient mice. This deficit occurs at the level of both the adrenal medulla (HSA axis) and the hypothalamus (HPA axis). PACAP-dependent transcriptional stress responses are conveyed through noncanonical cyclic AMP-and calcium-initiated signaling pathways within the HSA circuit. PACAP transcriptional regulation of the HPA axis, in the hypothalamus, is likely to be mediated via canonical cyclic AMP (cAMP) signaling through protein kinase A. Keywords PACAP; stress; HPA axisThe stress response may be defined operationally as the response of the neuroendocrine network to systemic or environmental perturbations outside of the normal physiological range. Stress responses in mammals are mediated through specific neural and neuroendocrine circuits. The propagation of signaling through these circuits is itself a cellular stressor. In other words, a 'stressed neuron' is one propagating an organismic stress response through a neuronal stress circuit. Thus, the cellular stress response is a point of entry to identifying targets for pharmacological modulation of organismic stress perception and processing.Neuropeptides play a special role in the stress response. As informational molecules stored in large dense-core vesicles, neuropeptides are released preferentially at higher firing rates, as occur during neurotransmission activated by stress in both the central and peripheral nervous systems. Fast and slow transmission are the two major modes of intercellular communication that underlie nervous system function. Fast transmission by glutamate, GABA, and acetylcholine involves direct gating of plasma membrane ionic channels for Correspondence: Lee E. Eiden, Section on Molecular Neuroscience, Laboratory of Cellular and Molecular Regulation, NIMH-IRP, NIH, Bethesda, Maryland 20892, eidenl@mail.nih.gov. This contribution summarizes the State-of-the-Art Lecture "Signaling in Stress: The 'emergency response' transcriptome" presented by L.E.E. at The 7 th International Congress of Neuroendocrinology, July 11-15, 2010, Rouen, France. NIH Public Access Author ManuscriptAnn N Y Acad Sci. Author manuscript; available in PMC 2012 March 1. Bloom et al. made the acute observation that neuropeptides represent the language of stress because the enhanced neuronal firing required to message systemic or environmen...