Early-life stress is a potent risk factor for development of psychiatric conditions such as depression. The underlying mechanisms remain poorly understood. Here, we used the early-life social isolation (ESI) model of early-life stress in rats to characterize development of depressive-like behavior, the role of microglia, levels of histone methylation, as well as expression of glutamate receptor subunits in the hippocampus. We found that depressive-like behavior was induced after ESI as determined by sucrose preference and forced swimming tests. Increased expression of microglial activation marker, Iba1, was observed in the hippocampus of the ESI group, while expression of the microglial CD200 receptor, which promotes microglial quiescence, significantly decreased. In addition, increased levels of proinflammatory cytokines, interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were observed in the hippocampus of the ESI group. Moreover, ESI increased levels of neuronal H3K9me2 (a repressive marker of transcription) and its associated "writer" enzymes, G9a and G9a-like protein, in the hippocampus. ESI also decreased expression of hippocampal NMDA receptor subunits, NR1, and AMPA receptor subunits, GluR1 and GluR2, which are involved in synaptic plasticity, but it did not affect expression of PSD95 and NR2B. Interestingly, treatment with minocycline to block microglial activation induced by ESI inhibited increases in hippocampal microglia and prevented ESI-induced depressive-like behavior as well as increases in IL-1β, IL-6, and TNF-α. Notably, minocycline also triggered downregulation of H3K9me2 expression and restored expression of NR1, GluR1, and GluR2. These results suggest that ESI induces depressive-like behavior, which may be mediated by microglial signaling.

Genetic variations in the vacuolar protein sorting 10 protein (Vps10p) family have been linked to Alzheimer’s disease (AD). Here we demonstrate deposition of fragments from the Vps10p member sortilin at senile plaques (SPs) in aged and AD human cerebrum. Sortilin changes were characterized in postmortem brains with antibodies against the extracellular and intracellular C-terminal domains. The two antibodies exhibited identical labeling in normal human cerebrum, occurring in the somata and dendrites of cortical and hippocampal neurons. The C-terminal antibody also marked extracellular lesions in some aged and all AD cases, appearing as isolated fibrils, mini-plaques, dense-packing or circular mature-looking plaques. Sortilin and β-amyloid (Aβ) deposition were correlated overtly in a region/lamina- and case-dependent manner as analyzed in the temporal lobe structures, with co-localized immunofluorescence seen at individual SPs. However, sortilin deposition rarely occurred around the pia, at vascular wall or in areas with typical diffuse Aβ deposition, with the labeling not enhanced by section pretreatment with heating or formic acid. Levels of a major sortilin fragment ~15 kDa, predicted to derive from the C-terminal region, were dramatically elevated in AD relative to control cortical lysates. Thus, sortilin fragments are a prominent constituent of the extracellularly deposited protein products at SPs in human cerebrum.

Background: Sepsis-associated encephalopathy (SAE) increases the mortality of septic patients, but its mechanism remains unclear. The present study aimed to investigate the roles of T lymphocytes, proBDNF, and their interaction in the pathogenesis of SAE. Methods: Fear conditioning tests were conducted for cognitive assessment in the lipopolysaccharide (LPS, 5 mg kg −1)-induced septic mice. Meninges and peripheral blood were harvested for flow cytometry or qPCR. FTY720 and monoclonal anti-proBDNF antibody (McAb-proB) were used to investigate the effect of lymphocyte depletion and blocking proBDNF on the impaired cognitive functions in the septic mice. Results: In the septic mice, cognitive function was impaired, the percentage of CD4 + T cells were decreased in the meninges (P = 0.0021) and circulation (P = 0.0222), and pro-inflammatory cytokines were upregulated, but the antiinflammatory cytokines interleukin (IL)-4 (P < 0.0001) and IL-13 (P = 0.0350) were downregulated in the meninges. Lymphocyte depletion by intragastrically treated FTY720 (1 mg kg −1) for 1 week ameliorated LPS-induced learning deficit. In addition, proBDNF was increased in the meningeal (P = 0.0042) and peripheral (P = 0.0090) CD4 + T cells. Intraperitoneal injection of McAb-proB (100 μg) before LPS treatment significantly alleviated cognitive dysfunction, inhibited the downregulation of meningeal (P = 0.0264) and peripheral (P = 0.0080) CD4 + T cells, and normalized the gene expression of cytokines in the meninges. However, intra-cerebroventricular McAb-proB injection (1 μg) did not have such effect. Finally, exogenous proBDNF downregulated the percentage of CD4 + T cells in cultured splenocytes from septic mice (P = 0.0021). Conclusion: Upregulated proBDNF in immune system promoted the pathogenesis of SAE through downregulating the circulating CD4 + T cells, limiting its infiltration into the meninges and perturbing the meningeal pro-/antiinflammatory homeostasis.

Rationale: Brain-derived neurotrophic factor precursor (proBDNF) is expressed in the central nervous system (CNS) and the immune system. However, the role of proBDNF in the pathogenesis of multiple sclerosis (MS) is unknown. Methods: Peripheral blood and post-mortem brain and spinal cord specimens were obtained from multiple sclerosis patients to analyze proBDNF expression in peripheral lymphocytes and infiltrating immune cells in the lesion site. The proBDNF expression profile was also examined in the experimental autoimmune encephalomyelitis (EAE) mouse model, and polyclonal and monoclonal anti-proBDNF antibodies were used to explore their therapeutic effect in EAE. Finally, the role of proBDNF in the inflammatory immune activity of peripheral blood mononuclear cells (PBMCs) was verified in vitro experiments. Results: High proBDNF expression was detected in the circulating lymphocytes and infiltrated inflammatory cells at the lesion sites of the brain and spinal cord in MS patients. In the EAE mouse model, proBDNF was upregulated in CNS and in circulating and splenic lymphocytes. Systemic but not intracranial administration of anti-proBDNF blocking antibodies attenuated clinical scores, limited demyelination, and inhibited proinflammatory cytokines in EAE mice. Immuno-stimulants treatment increased the proBDNF release and upregulated the expression of p75 neurotrophic receptors (p75 NTR ) in lymphocytes. The monoclonal antibody against proBDNF inhibited the inflammatory response of PBMCs upon stimulations. Conclusion: The findings suggest that proBDNF from immune cells promotes the immunopathogenesis of MS. Monoclonal Ab-proB may be a promising therapeutic agent for treating MS.