Metabolomics changes in brain-gut axis after unpredictable chronic mild stress.

BACKGROUND: Major depressive disorder is a leading cause of disability worldwide, affecting up to 17 % of the general population. The neural mechanisms of depression, however, are yet to be uncovered. Recently, attention has been drawn to the effects of dysfunctional brain-gut axis on depression, and many substances have been suggested to be involved in the communication between the gut and brain, such as ghrelin. METHODS: We herein systematically examined the changes of metabolomics after unpredictable chronic mild stress (UCMS)-induced depression-like behaviors in rats and compared the altered metabolites in the hippocampus and jejunum samples. RESULTS: Our results show that many metabolites significantly changed with UCMS both in the hippocampus and jejunum, such as L-glutamine, L-tyrosine, hydroxylamine, and 3-phosphoglyceric acid. Further studies suggested that these changes are the reasons for anxiety-like behaviors and depression-like behaviors in UCMS rats and also are the reasons for hippocampal neural plasticity. CONCLUSIONS: Coexistence of brain and gut metabolic changes in UCMS-induced depressive behavior in rats suggests a possible role of brain-gut axis in depression. This study provides insights into the neurobiology of depression.

Amyloid Beta Oligomers Target to Extracellular and Intracellular Neuronal Synaptic Proteins in Alzheimer's Disease.

Introduction: ß-Amyloid protein (Aß) putatively plays a seminal role in synaptic loss in Alzheimer's disease (AD). While there is no consensus regarding the synaptic-relevant species of Aß, it is known that Aß oligomers (AßOs) are noticeably increased in the early stages of AD, localizing at or within the synapse. In cell and animal models, AßOs have been shown to attach to synapses and instigate synapse dysfunction and deterioration. To establish the pathological mechanism of synaptic loss in AD, it will be important to identify the synaptic targets to which AßOs attach. Methods: An unbiased approach using far western ligand blots has identified three synaptic proteins to which AßOs specifically attach. These proteins (p100, p140, and p260) were subsequently enriched by detergent extraction, ultracentrifugation, and CHT-HPLC column separation, and sequenced by LC-MS/MS. P100, p140, and p260 were identified. These levels of AßOs targets in human AD and aging frontal cortexes were analyzed by quantitative proteomics and western-blot. The polyclonal antibody to AßOs was developed and used to block the toxicity of AßOs. The data were analyzed with one-way analysis of variance. Results: AßOs binding proteins p100, p140, and p260 were identified as Na/K-ATPase, synGap, and Shank3, respectively. α3-Na/K-ATPase, synGap, and Shank3 proteins showed loss in the postsynaptic density (PSD) of human AD frontal cortex. In short term experiments, oligomers of Aß inhibited Na/K-ATPase at the synapse. Na/K-ATPase activity was restored by an antibody specific for soluble forms of Aß. α3-Na/K-ATPase protein and synaptic ß-amyloid peptides were pulled down from human AD synapses by co-immunoprecipitation. Results suggest synaptic dysfunction in early stages of AD may stem from inhibition of Na/K-ATPase activity by Aß oligomers, while later stages could hypothetically result from disrupted synapse structure involving the PSD proteins synGap and Shank3. Conclusion: We identified three AßO binding proteins as α3-Na/K-ATPase, synGap, and Shank3. Soluble Aß oligomers appear capable of attacking neurons via specific extracellular as well as intracellular synaptic proteins. Impact on these proteins hypothetically could lead to synaptic dysfunction and loss, and could serve as novel therapeutic targets for AD treatment by antibodies or other agents.

Effect of intraperitoneal or intracerebroventricular injection of streptozotocin on learning and memory in mice.

Alteration of behavior and PSD proteins in cerebral cortex and hippocampal synaptosome in the Alzheimer's disease (AD) mouse model were determined. AD was established by intraperitoneal injection of streptozotocin (STZ) in neonatal mice (intraperitoneal AD group) or intracerebroventricular injection of STZ in adult mice (intracerebroventricular AD group). Body weight and blood sugar level were measured. Following Morris water maze (MWM) test and fear-conditioning test, cerebral cortex and hippocampus tissues were collected and the levels of PSD95 and shank3 proteins in these tissues were measured by western blot analysis. The body weight was reduced and the blood sugar concentration was increased in the intraperitoneal AD group compared with the control group. In contrast, the body weight was reduced, while the blood sugar concentration was not increased in the intracerebroventricular AD group compared with the control group. Escape latency in both AD groups was extended compared with the control group. The freezing time in the intraperitoneal AD group was increased, while in the intracerebroventricular AD group, the freezing time was reduced. PSD95 and shank3 proteins in the cerebral cortex in both AD groups were decreased compared with the control group. PSD95 in the hippocampus was reduced in both AD groups compared with the control group. Shank3 in the hippocampus in the intracerebroventricular AD group was significantly reduced compared with the control group. Intraperitoneal injection of STZ in neonatal mice led to elevated blood sugar, impaired spatial memory and enhanced emotional memory when they become adults. In contrast, intracerebroventricular injection of STZ in adults directly led to deteriorated spatial and emotional memory without alteration of blood sugar content, which could be associated with the changes of PSD95 and shank3 proteins in hippocampus.