Brain Peptides Research Articles

Tribute to Roger Guillemin, a pioneer in neuroendocrinology (1924-2024), Nobel Prize in Physiology or Medicine.

Roger Guillemin discovered and characterized the hypothalamic factors that control anterior pituitary functions. He consequently demonstrated that these brain peptides regulate a large number of major body activities through neuroendocrine mechanisms. This especially include growth, fertility and reproduction, endocrine gland functions and stress. These seminal works paved the way to major applications in many fields of physiology and medicine for diagnosis, pharmacology and therapy, far beyond the initial discovery and properties of these molecules, including in cancerology, immunology, inflammation, drug addiction and behavior.

Pathological Defects in a Drosophila Model of Alzheimer's Disease and Beneficial Effects of the Natural Product Lisosan G.

Alzheimer's disease (AD) brains are histologically marked by the presence of intracellular and extracellular amyloid deposits, which characterize the onset of the disease pathogenesis. Increasing evidence suggests that certain nutrients exert a direct or indirect effect on amyloid β (Aβ)-peptide production and accumulation and, consequently, on AD pathogenesis. We exploited the fruit fly Drosophila melanogaster model of AD to evaluate in vivo the beneficial properties of Lisosan G, a fermented powder obtained from organic whole grains, on the intracellular Aβ-42 peptide accumulation and related pathological phenotypes of AD. Our data showed that the Lisosan G-enriched diet attenuates the production of neurotoxic Aβ peptides in fly brains and reduces neuronal apoptosis. Notably, Lisosan G exerted anti-oxidant effects, lowering brain levels of reactive oxygen species and enhancing mitochondrial activity. These aspects paralleled the increase in autophagy turnover and the inhibition of nucleolar stress. Our results give support to the use of the Drosophila model not only to investigate the molecular genetic bases of neurodegenerative disease but also to rapidly and reliably test the efficiency of potential therapeutic agents and diet regimens.

Evaluation Left Ventricle Performance in hypertensive patients using heart ultrasound and levels of a salt-producing brain peptide in blood

Background: we studied on 100 patients in total, with 56 in the 'LV dysfunction' group and the rest in the 'control' group to evaluate of left ventricular functioning in hypertensive patients by examining the ultrasound of the heart by tracking the scores and their association with levels of a salt-producing brain peptide in the blood. . To find relevant research, a thorough online search was conducted. Data were retrieved and synthesized from the included studies after they were evaluated for quality and risk of bias. The findings demonstrated a robust association between B-type natriuretic peptide (BNP) levels and speckle-tracking echocardiography (STE) derived indices of left ventricular (LV) performance in hypertension individuals. The findings of this review highlight the potential of STE as a valuable tool for evaluating LV performance in hypertensive patients and its association with BNP levels in Baghdad. Aim: This study aims to find out how hypertension patients' LV function, as determined by speckle-tracking echocardiography (STE), correlated with B-type natriuretic peptide BNP levels in the blood. Methods: All subjects had echocardiographic tests using a commercially available ultrasonography equipment equipped with a phased-array transducer operating at 3.5 MHz, with the following parameters measured: Biplane with a few tweaks for this study, the LVEF was calculated using Simpson's method ,the left ventricular systolic volume (SV) ,systolic volume at the end of the left ventricle (LVESV), in order to determine the LVMI, the Devereux formula was used and the filling ratio of early to late diastole (E/A ratio). They were compared with a healthy group (control) to obtain accurate results. Results: There were statistically significant differences in LVEF, LVEDV, LVESV, LVMI, E/A ratio, E/e' ratio, and global longitudinal strain (GLS) between the control and LV dysfunction groups. Diastolic dysfunction was more common in LV dysfunction patients, and they also had lower GLS values than the control group. The levels of BNP were shown to have a favorable relationship with numerous echocardiographic parameters. Hypertensive individuals had greater BNP levels than the control group. The LVH group also had greater levels of BNP than the non-LVH group.

Variants in the MS4A cluster interact with soluble TREM2 expression on biomarkers of neuropathology

Recent evidence suggests that Alzheimer’s disease (AD) genetic risk variants (rs1582763 and rs6591561) of the MS4A locus are genome-wide significant regulators of soluble TREM2 levels such that the minor allele of the protective variant (rs1582763) is associated with higher sTREM2 and lower AD risk while the minor allele of (rs6591561) relates to lower sTREM2 and higher AD risk. Our group previously found that higher sTREM2 relates to higher Aβ40, worse blood–brain barrier (BBB) integrity (measured with the CSF/plasma albumin ratio), and higher CSF tau, suggesting strong associations with amyloid abundance and both BBB and neurodegeneration complicate interpretation. We expand on this work by leveraging these common variants as genetic tools to tune the interpretation of high CSF sTREM2, and by exploring the potential modifying role of these variants on the well-established associations between CSF sTREM2 as well as TREM2 transcript levels in the brain with AD neuropathology. Biomarker analyses leveraged data from the Vanderbilt Memory & Aging Project (n = 127, age = 72 ± 6.43) and were replicated in the Alzheimer’s Disease Neuroimaging Initiative (n = 399, age = 73 ± 7.39). Autopsy analyses were performed leveraging data from the Religious Orders Study and Rush Memory and Aging Project (n = 577, age = 89 ± 6.46). We found that the protective variant rs1582763 attenuated the association between CSF sTREM2 and Aβ40 (β = -0.44, p-value = 0.017) and replicated this interaction in ADNI (β = -0.27, p = 0.017). We did not observe this same interaction effect between TREM2 mRNA levels and Aβ peptides in brain (Aβ total β = -0.14, p = 0.629; Aβ1-38, β = 0.11, p = 0.200). In contrast to the effects on Aβ, the minor allele of this same variant seemed to enhance the association with blood–brain barrier dysfunction (β = 7.0e-4, p = 0.009), suggesting that elevated sTREM2 may carry a much different interpretation in carriers vs. non-carriers of this allele. When evaluating the risk variant (rs6591561) across datasets, we did not observe a statistically significant interaction against any outcome in VMAP and observed opposing directions of associations in ADNI and ROS/MAP on Aβ levels. Together, our results suggest that the protective effect of rs1582763 may act by decoupling the associations between sTREM2 and amyloid abundance, providing important mechanistic insight into sTREM2 changes and highlighting the need to incorporate genetic context into the analysis of sTREM2 levels, particularly if leveraged as a clinical biomarker of disease in the future.

Structural insights into the potential binding sites of Cathepsin D using molecular modelling techniques

Alzheimer’s disease (AD) is the most prevalent type of dementia caused by the accumulation of amyloid beta (Aβ) peptides. The extracellular deposition of Aβ peptides in human AD brain causes neuronal death. Therefore, it has been found that Aβ peptide degradation is a possible therapeutic target for AD. CathD has been known to breakdown amyloid beta peptides. However, the structural role of CathD is not yet clear. Hence, for the purpose of gaining a deeper comprehension of the structure of CathD, the present computational investigation was performed using virtual screening technique to predict CathD's active site residues and substrate binding mode. Ligand-based virtual screening was implemented on small molecules from ZINC database against crystal structure of CathD. Further, molecular docking was utilised to investigate the binding mechanism of CathD with substrates and virtually screened inhibitors. Localised compounds obtained through screening performed by PyRx and AutoDock 4.2 with CathD receptor and the compounds having highest binding affinities were picked as; ZINC00601317, ZINC04214975 and ZINCC12500925 as our top choices. The hydrophobic residues Viz. Gly35, Val31, Thr34, Gly128, Ile124 and Ala13 help stabilising the CathD-ligand complexes, which in turn emphasises substrate and inhibitor selectivity. Further, MM-GBSA approach has been used to calculate binding free energy between CathD and selected compounds. Therefore, it would be beneficial to understand the active site pocket of CathD with the assistance of these discoveries. Thus, the present study would be helpful to identify active site pocket of CathD, which could be beneficial to develop novel therapeutic strategies for the AD.

Aging and brain free cholesterol concentration on amyloid-β peptide accumulation in guinea pigs.

Alzheimer's disease is a complex multifactorial neurodegenerative disorder wherein age is a major risk factor. The appropriateness of the Hartley guinea pig (GP), which displays high sequence homologies of its amyloid-β (Aβ40 and Aβ42) peptides, Mdr1 and APP(amyloid precursor protein) and similarity in lipid handling to humans, was appraised among 9-40weeks old guinea pigs. Protein expression levels of P-gp (Abcb1) and Cyp46a1 (24(S)-hydroxylase) for Aβ40, and Aβ42 efflux and cholesterol metabolism, respectively, were decreased with age, whereas those for Lrp1 (low-density lipoprotein receptor related protein 1), Rage (receptor for advanced glycation endproducts) for Aβ efflux and influx, respectively, and Abca1 (the ATP binding cassette subfamily A member 1) for cholesterol efflux, were unchanged among the ages examined. There was a strong, negative correlation of the brain Aβ peptide concentrations and Abca1 protein expression levels with free cholesterol. The correlation of Aβ peptide concentrations with Cyp46a1 was, however, not significant, and concentrations of the 24(S)-hydroxycholesterol metabolite revealed a decreasing trend from 20weeks old toward 40weeks old guinea pigs. The composite data suggest a role for free cholesterol on brain Aβ accumulation. The decreases in P-gp and Lrp1 protein levels should further exacerbate the accumulation of Aβ peptides in guinea pig brain.

β-Amyloid peptide modulates peripheral immune responses and neuroinflammation in rats.

Alzheimer's disease (AD) is characterized by immune system dysregulation, impacting both central and peripheral immune responses. The study aimed to investigate the mechanism behind the neurotoxic effects of β-amyloid (Aβ) peptide in the rat brain including the study of neuroinflammation, neurodegeneration, and alterations in peripheral immune responses (PIR). The neuroinflammation brought on by Aβ1-42 and is unknown to influence PIR. Animal models were prepared, after 28 days, control, sham, and treated rats were anaesthetized and inflammatory markers of hippocampus and serum levels (reactive oxygen species, nitrite, tumor necrosis factor-α, and interleukin-1β), and some markers of PIR (splenic mononuclear cells or MNC, cytotoxicity and phagocytic index of the white blood cells leukocyte adhesion inhibition index or LAI), as well as polymorphonuclear cells of the spleen, were assessed. In addition to changes in peripheral immune responses, the present study found that AD rats had higher blood levels of inflammatory markers. Based on the study, the immune system irregularities observed in AD rats in the peripheral regions might be connected to neuroinflammation, which is facilitated by a compromised blood-brain barrier. Hence, it is viable to propose that the neuroinflammatory condition in rats with Aβ-induced AD could modify immune responses in the peripheral areas with significantly higher levels of inflammatory cytokines markers in the hippocampal tissue in Aβ-injected AD rats.

Integrating a Multi-label Deep Learning Approach with Protein Information to Compare Bioactive Peptides in Brain and Plasma.

Peptide therapeutics is gaining momentum. Advances in the field of peptidomics have enabled researchers to harvest vital information from various organisms and tissue types concerning peptide existence, expression and function. The development of mass spectrometry techniques for high-throughput peptide quantitation has paved the way for the identification and discovery of numerous known and novel peptides. Though much has been achieved, scientists are still facing difficulties when it comes to reducing the search space of the large mass spectrometry-generated peptidomics datasets and focusing on the subset of functionally relevant peptides. Moreover, there is currently no straightforward way to analytically compare the distributions of bioactive peptides in distinct biological samples, which may reveal much useful information when seeking to characterize tissue- or fluid-specific peptidomes. In this chapter, we demonstrate how to identify, rank, and compare predicted bioactive peptides and bioactivity distributions from extensive peptidomics datasets. To aid this task, we utilizeMultiPep, a multi-label deep learning approach designed for classifying peptide bioactivities, to identify bioactive peptides. The predicted bioactivities are synergistically combined with protein information from the UniProt database, which assist in navigating through the jungle of putative therapeutic peptides and relevant peptide leads.

Intracerebral inoculation of healthy non-transgenic rats with a single aliquot of oligomeric amyloid-β (1-42) profoundly and progressively alters brain function throughout life.

One of the puzzling aspects of sporadic Alzheimer's disease (AD) is how it commences. Changes in one key brain peptide, amyloid-beta (Aβ), accompany disease progression, but whether this comprises a trigger or a consequence of AD is still a topic of debate. It is clear however that the cerebral presence of oligomeric Aβ (1-42) is a key factor in early AD-pathogenesis. Furthermore, treatment of rodent brains with oligomeric Aβ (1-42) either in vitro or in vivo, acutely impairs hippocampal synaptic plasticity, creating a link between Aβ-pathology and learning impairments. Here, we show that a once-off inoculation of the brains of healthy adult rats with oligomeric Aβ (1-42) exerts debilitating effects on the long-term viability of the hippocampus, one of the primary targets of AD. Changes are progressive: months after treatment, synaptic plasticity, neuronal firing and spatial learning are impaired and expression of plasticity-related proteins are changed, in the absence of amyloid plaques. Early changes relate to activation of microglia, whereas later changes are associated with a reconstruction of astroglial morphology. These data suggest that a disruption of Aβ homeostasis may suffice to trigger an irreversible cascade, underlying progressive loss of hippocampal function, that parallels the early stages of AD.

Kisspeptin levels in polycystic ovary syndrome and its manifestations

Background: The altered luteinizing hormone to follicle-stimulating hormone (LH/FSH) ratio- an important component in the pathogenesis of polycystic ovary syndrome (PCOS), is regulated by a brain peptide kisspeptin. This study aimed to explore the association of serum kisspeptin levels with PCOS and its manifestations. Methods: This cross-sectional study included 80 participants with PCOS on the basis of International evidence-based guidelines, 2018, and 71 healthy matched controls. Along with clinical information, fasting blood was drawn to measure total testosterone, sex hormone binding globulin, thyroid stimulating hormone, prolactin, 17-hydroxyprogesterone, and kisspeptin in all, and glucose, lipids, insulin, LH, FSH in only PCOS participants in the follicular phase of the menstrual cycle. Kisspeptin was measured by sandwiched enzyme-linked immunosorbent assay method with a lower limit detection level of 0.01 pg/mL. Result: Kisspeptin levels were undetectable in 25 out of 80 and 16 out of 71 controls. Among the participants with detection levels (55 in each group), kisspeptin did not differ between PCOS and control [31.2 (19.2 – 43.1) vs. 40.4 (14.9 – 70.4), pg/mL, p=0.446]. Among participants with PCOS, kisspeptin levels had no significant associations or correlations with any manifestations (ns for all). ROC curve analysis showed kisspeptin as not an acceptable marker for PCOS [AUC (95% CI): 0.57 (0.46 – 0.68), p= 0.221]. Conclusion: Our study failed to show any association of kisspeptin levels with PCOS and its manifestations.

Inhibition of insulin-degrading enzyme in human neurons promotes amyloid-β deposition.

Alzheimer's disease (AD) is characterised by the aggregation and deposition of amyloid-β (Aβ) peptides in the human brain. In age-related late-onset AD, deficient degradation and clearance, rather than enhanced production, of Aβ contributes to disease pathology. In the present study, we assessed the contribution of the two key Aβ-degrading zinc metalloproteases, insulin-degrading enzyme (IDE) and neprilysin (NEP), to Aβ degradation in human induced pluripotent stem cell (iPSC)-derived cortical neurons. Using an Aβ fluorescence polarisation assay, inhibition of IDE but not of NEP, blocked the degradation of Aβ by human neurons. When the neurons were grown in a 3D extracellular matrix to visualise Aβ deposition, inhibition of IDE but not NEP, increased the number of Aβ deposits. The resulting Aβ deposits were stained with the conformation-dependent, anti-amyloid antibodies A11 and OC that recognise Aβ aggregates in the human AD brain. Inhibition of the Aβ-forming β-secretase prevented the formation of the IDE-inhibited Aβ deposits. These data indicate that inhibition of IDE in live human neurons grown in a 3D matrix increased the deposition of Aβ derived from the proteolytic cleavage of the amyloid precursor protein. This work has implications for strategies aimed at enhancing IDE activity to promote Aβ degradation in AD.

IMD signaling in the gut and the brain modulates Amyloid-beta-induced deficits in Drosophila

AimsEvidence indicates accumulating Aβ peptides in brain activates immune responses in neuronal and peripheral system, which may collaboratively influence pathogenesis of Alzheimer's disease (AD). We aim to investigate whether regulating intestinal innate immune signaling ameliorates Aβ-induced impairments in Drosophila melanogaster. Main methodsQuantitative polymerase chain reaction (qPCR) was used to observe expression changes of innate immune responses related genes in brain and in gut under the circumstance of Aβ overexpressing in nerve system. Aversive olfactory conditioning and survival assay were used to investigate effects of modulating Attacin-A (AttA) and Dpitercin-A (DptA). Fluorometric assays of respiratory burst activity was introduced to explore whether reducing oxidative stress enables overexpressing intestinal AttA and DptA to reverse Aβ-induced deficits. Key findingsIn vivo genetic analysis revealed that accumulating Aβ42 in neurons modulates innate immune signaling of the IMD pathway both in the brain and in the gut. Increased expression levels of the intestinal AttA and DptA improved learning performance and extended the lifespan of Aβ42 flies. The administration of apramycin led to alleviations of Aβ-induced behavioral changes, indicating that gram-negative bacteria are associated with the development of Aβ-induced pathologies. Further analysis showed that the neural expression of Aβ42 increased oxidative stress in the gut, which disrupted intestinal integrity and decreased learning performance. In addition, increased levels of AMPs targeting gram-negative bacteria and antioxidants reduced oxidative stress in the gut and reversed Aβ-induced behavioral damage. SignificanceThese findings suggest that innate immune responses in the gut play a pivotal role in modulating Aβ-induced pathologies.

Study on toxicity responses and their mechanisms in Xenopus tropicalis long-term exposure to Shigella flexneri and ciprofloxacin

The abuse and overuse of antibiotics increased not only the exposure of aquatic animals to antibiotics but also the development of resistance in pathogenic bacteria. To investigate the effects and mechanisms of exposure, a long-term experiment lasting 120 days was conducted in which Xenopus tropicalis was exposed to single and combined stress factors of multiresistant pathogenic Shigella flexneri and ciprofloxacin (CIP). The intestinal oxidative stress, immune factors and flora, as well as the brain-gut axis correlation factors of X. tropicalis, were tracked to account for the response of aquatic animals to the exogenous pollutants. SOD activity and MDA content were significantly increased in stressed X. tropicalis (p < 0.001), while the levels of proinflammatory factors (IL-1β, IFN-γ) were significantly reduced (p < 0.01). The content of intestinal beneficial bacteria decreased and that of harmful bacteria increased in the intestinal flora of the stressed X. tropicalis (p < 0.001). These results suggested that S. flexneri and CIP disturbed the intestinal flora and caused oxidative damage in the host, and the body produced a series of responses, such as oxidative stress responses and regulation of the expression of immune factors, to maintain the balance of antioxidant inflammation. Significant changes in the expression of intestinal neurotransmitters (5-HT, CGRP) and brain peptides (BDNF, NCAM, NPY) (p < 0.05) also indicated that the brain-gut axis interaction was disrupted. In addition, although the coexisting CIP could reduce intestinal toxicity caused by S. flexneri, the amount of intestinal pathogenic bacteria Desulfovibrio increased significantly. Moreover, compared with the single exposure group, SOD activity, CAT activity and MDA content were significantly reduced in the dual exposure group. Therefore, the health risks of multiresistant pathogenic bacteria on the intestinal and brain-gut axis interaction should be given more attention, and the interaction of brain-gut axis is more important when antibiotics coexist.

Brain Hydrophobic Peptides Antagonists of Neurotoxic Amyloid β Peptide Monomers/Oligomers-Protein Interactions.

Amyloid β (Aβ) oligomers have been linked to Alzheimer's disease (AD) pathogenesis and are the main neurotoxic forms of Aβ. This review focuses on the following: (i) the Aβ(1-42):calmodulin interface as a model for the design of antagonist Aβ peptides and its limitations; (ii) proteolytic degradation as the major source of highly hydrophobic peptides in brain cells; and (iii) brain peptides that have been experimentally demonstrated to bind to Aβ monomers or oligomers, Aβ fibrils, or Aβ plaques. It is highlighted that the hydrophobic amino acid residues of the COOH-terminal segment of Aβ(1-42) play a key role in its interaction with intracellular protein partners linked to its neurotoxicity. The major source of highly hydrophobic endogenous peptides of 8-10 amino acids in neurons is the proteasome activity. Many canonical antigen peptides bound to the major histocompatibility complex class 1 are of this type. These highly hydrophobic peptides bind to Aβ and are likely to be efficient antagonists of the binding of Aβ monomers/oligomers concentrations in the nanomolar range with intracellular proteins. Also, their complexation with Aβ will protect them against endopeptidases, suggesting a putative chaperon-like physiological function for Aβ that has been overlooked until now. Remarkably, the hydrophobic amino acid residues of Aβ responsible for the binding of several neuropeptides partially overlap with those playing a key role in its interaction with intracellular protein partners that mediates its neurotoxicity. Therefore, these latter neuropeptides are also potential candidates to antagonize Aβ peptides binding to target proteins. In conclusion, the analysis performed in this review points out that hydrophobic endogenous brain neuropeptides could be valuable biomarkers to evaluate the risk of the onset of sporadic AD, as well as for the prognosis of AD.

Modulation of aggregation and structural polymorphisms of β-amyloid fibrils in cellular environments by pyroglutamate-3 variant cross-seeding

Amyloidogenic deposition of β-amyloid (Aβ) peptides in human brain involves not only the wild-type Aβ (wt-Aβ) sequences, but also posttranslationally modified Aβ (PTM-Aβ) variants. Recent studies hypothesizes that the PTM-Aβ variants may trigger the deposition of wt-Aβ, which underlies the pathology of Sporadic Alzheimer's disease. Among PTM-Aβ variants, the pyroglutamate-3-Aβ (pyroE3-Aβ) has attracted much attention because of their significant abundances and broad distributions in senile plaques and dispersible and soluble oligomers. pyroE3-specific antibodies are being tested as potential anti-Aβ drugs in clinical trials. However, evidence that support the triggering effect of pyroE3-Aβ on wt-Aβ in cells remain lacking, which diminishes its pathological relevance. We show here that cross-seeding with pyroE3-Aβ40 leads to accelerated extracellular and intracellular aggregation of wt-Aβ40 in different neuronal cells. Cytotoxicity levels are elevated through the cross-seeded aggregation, comparing with the self-seeded aggregation of wt-Aβ40 or the static presence of pyroE3-Aβ40 seeds. For the extracellular deposition in mouse neuroblastoma Neuro2a (N2a) cells, the cytotoxicity elevation correlates positively with the seeding efficiency. Besides aggregation rates, cross-seeding with pyroE3-Aβ40 also modulates the molecular level structural polymorphisms of the resultant wt-Aβ40 fibrils. Using solid-state nuclear magnetic resonance (ssNMR) spectroscopy, we identified key structural differences between the parent pyroE3/ΔE3 and wt-Aβ40 fibrils within their fibrillar cores. Structural propagation from seeds to daughter fibrils is demonstrated to be more pronounced in the extracellular seeding in N2a cells by comparing the ssNMR spectra from different seeded wt-Aβ40 fibrils, but less significant in the intracellular seeding process in human neuroblastoma SH-SY5Y cells.

Cannabidiol tempers alcohol intake and neuroendocrine and behavioural correlates in alcohol binge drinking adolescent rats. Focus on calcitonin gene-related peptide's brain levels.

Alcohol binge drinking is common among adolescents and may challenge the signalling systems that process affective stimuli, including calcitonin gene-related peptide (CGRP) signalling. Here, we employed a rat model of adolescent binge drinking to evaluate reward-, social- and aversion-related behaviour, glucocorticoid output and CGRP levels in affect-related brain regions. As a potential rescue, the effect of the phytocannabinoid cannabidiol was explored. Adolescent male rats underwent the intermittent 20% alcohol two-bottle choice paradigm; at the binge day (BD) and the 24 h withdrawal day (WD), we assessed CGRP expression in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, hypothalamus and brainstem; in addition, we evaluatedsucrose preference, social motivation and drive, nociceptive response, and serum corticosterone levels. Cannabidiol (40 mg/kg, i.p.) was administered before each drinking session, and its effect was measured on the above-mentioned readouts. At BD and WD, rats displayed decreased CGRP expression in mPFC, NAc and amygdala; increased CGRP levels in the brainstem; increased response to rewarding- and nociceptive stimuli and decreased social drive; reduced serum corticosterone levels. Cannabidiol reduced alcohol consumption and preference; normalised the abnormal corticolimbic CGRP expression, and the reward and aversion-related hyper-responsivity, as well as glucocorticoid levels in alcohol binge-like drinking rats. Overall, CGRP can represent both a mediator and a target of alcohol binge-like drinking and provides a further piece in the intricate puzzle of alcohol-induced behavioural and neuroendocrine sequelae. CBD shows promising effects in limiting adolescent alcohol binge drinking and rebalancing the bio-behavioural abnormalities.

Quercetin Exerts a Protective Effect on Ischemic Stroke-induced Memory Deficits in Mice

Objectives Brain injury resulting from an ischemic stroke affects cognitive performance by disrupting the hippocampus. Several processes are involved in brain injury progression, including inflammation, glutamate excitotoxicity, and modulated brain peptide systems such as the melanocortin system. Reports show that quercetin exerts neuroprotective activity. This study investigates quercetin’s role in the cognitive function of ischemic stroke-induced mice and the possible mechanisms involved. Materials and Methods ICR mice were used. The left unilateral common carotid artery occlusion was conducted for 4 h to induce an ischemic stroke in the mice. Quercetin 50, 100, and 200 mg/kg were administered to separate groups intraperitoneally for 7 days. Cognitive function was examined using the T-maze test. The hippocampal mRNA expressions of NR2A, NR2B, melanocortin 4 receptor (MC4R), pro-opiomelanocortin precursors (POMC), and nuclear factor 2 (Nrf2) were examined using reverse transcription-polymerase chain reaction. Results It was found that stroke disrupted cognitive function. Quercetin administration ameliorated cognitive impairment. Quercetin attenuated the stroke-induced decrease in MC4R mRNA expression. Moreover, quercetin suppressed the stroke-induced increase in the hippocampal mRNA expression of NR2A. Conclusion Quercetin ameliorates cognitive deficits and normalizes impaired hippocampal melanocortin and glutamatergic signaling in ischemic stroke-induced mice.

Mass Spectrometry Imaging in Alzheimer's Disease.

Introduction: Amyloid-beta (Aβ) pathology is the precipitating histopathological characteristic of Alzheimer's disease (AD). Although the formation of amyloid plaques in human brains is suggested to be a key factor in initiating AD pathogenesis, it is still not fully understood the upstream events that lead to Aβ plaque formation and its metabolism inside the brains. Methods: Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) has been successfully introduced to study AD pathology in brain tissue both in AD mouse models and human samples. By using MALDI-MSI, a highly selective deposition of Aβ peptides in AD brains with a variety of cerebral amyloid angiopathy (CAA) involvement was observed. Results: MALDI-MSI visualized depositions of shorter peptides in AD brains; Aβ1-36 to Aβ1-39 were quite similarly distributed with Aβ1-40 as a vascular pattern, and deposition of Aβ1-42 and Aβ1-43 was visualized with a distinct senile plaque pattern distributed in parenchyma. Moreover, how MALDI-MSI covered in situ lipidomics of plaque pathology has been reviewed, which is of interest as aberrations in neuronal lipid biochemistry have been implicated in AD pathogenesis. Discussion: In this study, we introduce the methodological concepts and challenges of MALDI-MSI for the studies of AD pathogenesis. Diverse Aβ isoforms including various C- and N-terminal truncations in AD and CAA brain tissues will be visualized. Despite the close relationship between vascular and plaque Aβ deposition, the current strategy will define cross talk between neurodegenerative and cerebrovascular processes at the level of Aβ metabolism.

Identification of GnRH-like peptide and its potential signaling pathway involved in the oocyte meiotic maturation in the Chinese mitten crab, Eriocheir sinensis

Gonadotropin-releasing hormone (GnRH) plays a pivotal role in reproductive regulation in vertebrates. However, GnRH was rarely isolated and its function remains poorly characterized in invertebrates. The existence of GnRH in ecdysozoa has been controversial for a long. Here, we isolated and identified two GnRH-like peptides from brain tissues in Eriocheir sinensis. Immunolocalization showed that the presence of EsGnRH-like peptide in brain, ovary and hepatopancreas. Synthetic EsGnRH-like peptides can induce germinal vesicle breakdown (GVBD) of oocyte. Similar to vertebrates, ovarian transcriptomic analysis revealed a GnRH signaling pathway in the crab, in which most genes exhibited dramatically high expression at GVBD. RNAi knockdown of EsGnRHR suppressed the expression of most genes in the pathway. Co-transfection of the expression plasmid for EsGnRHR with reporter plasmid bearing CRE-luc or SRE-luc response element into 293T cells showed that EsGnRHR transduces its signal via cAMP and Ca2+ signaling transduction pathways. In vitro incubation of the crab oocyte with EsGnRH-like peptide confirmed the cAMP-PKA cascade and Ca2+ mobilization signaling cascade but lack of a PKC cascade. Our data present the first direct evidence of the existence of GnRH-like peptides in the crab and demonstrated its conserved role in the oocyte meiotic maturation as a primitive neurohormone.

Brain p3‐Alcβ peptide restores neuronal viability impaired by Alzheimer's amyloid β‐peptide

We propose a new therapeutic strategy for Alzheimer's disease (AD). Brain peptide p3‐Alcβ37 is generated from the neuronal protein alcadein β through cleavage of γ‐secretase, similar to the generation of amyloid β (Aβ) derived from Aβ‐protein precursor/APP. Neurotoxicity by Aβ oligomers (Aβo) is the prime cause prior to the loss of brain function in AD. We found that p3‐Alcβ37 and its shorter peptide p3‐Alcβ9‐19 enhanced the mitochondrial activity of neurons and protected neurons against Aβo‐induced toxicity. This is due to the suppression of the Aβo‐mediated excessive Ca2+ influx into neurons by p3‐Alcβ. Successful transfer of p3‐Alcβ9‐19 into the brain following peripheral administration improved the mitochondrial viability in the brain of AD mice model, in which the mitochondrial activity is attenuated by increasing the neurotoxic human Aβ42 burden, as revealed through brain PET imaging to monitor mitochondrial function. Because mitochondrial dysfunction is common in the brain of AD patients alongside increased Aβ and reduced p3‐Alcβ37 levels, the administration of p3‐Alcβ9‐19 may be a promising treatment for restoring, protecting, and promoting brain functions in patients with AD.