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1.
Neurosci Biobehav Rev ; : 105810, 2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-39009293

RESUMO

Sleep disturbances, encompassing altered sleep physiology or disorders like insomnia and sleep apnea, profoundly impact physiological functions and elevate disease risk. Despite extensive research, the underlying mechanisms and sex-specific differences in sleep disorders remain elusive. While polysomnography serves as a cornerstone for human sleep studies, animal models provide invaluable insights into sleep mechanisms. However, the availability of animal models of sleep disorders is limited, with each model often representing a specific sleep issue or mechanism. Therefore, selecting appropriate animal models for sleep research is critical. Given the significant sex differences in sleep patterns and disorders, incorporating both male and female subjects in studies is essential for uncovering sex-specific mechanisms with clinical relevance. This review provides a comprehensive overview of various rodent models of sleep disturbance, including sleep deprivation, sleep fragmentation, and circadian rhythm dysfunction. We evaluate the advantages and disadvantages of each model and discuss sex differences in sleep and sleep disorders, along with potential mechanisms. We aim to advance our understanding of sleep disorders and facilitate sex-specific interventions.

2.
Int J Surg Pathol ; : 10668969241226705, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321782

RESUMO

BACKGROUND: PSMA (prostate-specific membrane antigen) is a type II transmembrane glycoprotein recently found to be expressed in hepatocellular carcinoma (HCC). We aimed to characterize the expression pattern of PSMA in HCC and its association with clinicopathologic parameters and other biomarkers. METHODS: Immunohistochemical studies for PSMA were performed on a previously established tissue microarray of 103 surgically resected HCC. RESULTS: Conceivable PSMA expression in ≥5% tumor-associated vasculature (TAV) was considered positive, and was identified in 56 (54.4%) tumors. Eight (7.8%) tumors also showed membranous/cytoplasmic and/or canalicular staining in tumor cells. By chi-square tests, only PSMA-positive TAV was associated with moderate-to-poorly differentiated HCC and the modified higher tumor stage (P < .05). PSMA-positive TAV was not associated with age, sex, or expression of glypican-3, keratin 7, CD3, CD8, HHLA-2, but marginally correlated with programmed death-ligand 1 (PD-L1) expression (P = .052). Kaplan-Meier survival analysis revealed PSMA-positive TAV as an independent risk factor for poorer disease-specific survival (P = .008). Co-expression of PD-L1 did not ameliorate the adverse prognostication of PSMA-positive TAV. Membranous/cytoplasmic/canalicular expression of PSMA alone was not prognostically significant. CONCLUSIONS: Our study confirmed that PSMA-positive TAV is a prospective diagnostic and prognostic biomarker for HCC. Co-expression of PSMA with PD-L1 may suggest potential crosstalk between the 2 proteins, likely regulating the tumor microenvironment.

3.
Ann Diagn Pathol ; 69: 152250, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38142627

RESUMO

Appendiceal neuroendocrine neoplasms (NENs) can present with various growth patterns including the traditional triad of histologic patterns-insular, trabecular and tubular. A small cluster pattern was also found in this study and the literature on this specific morphology is limited. In this study, we conducted a comprehensive review of appendiceal NENs from our institution over a ten-year period. Clinical and demographic data were obtained from medical records. Immunohistochemical stains were performed with antibodies specific for synaptophysin, chromogranin, INSM1, CD56, serotonin and peptide YY. The small cluster pattern was found in 29.4 % of all cases evaluated. The tumor cells in these cases were predominantly located at the distal tip of the appendix, associated with fibrous obliteration. These tumors were smaller in size and tended towards less advanced tumor stage, with reduced incidence of lymphovascular and/or perineural invasion. Chromogranin expression was identified in 76 % of these cases. There is a heterogeneous hormone profile with 46.7 % serotonin and 33.3 % peptide YY. In conclusion, the small cluster pattern NENs present with unique histological features and hormone expression profile. Among the various neuroendocrine markers, INSM1 showed superior diagnostic performance, with high sensitivity and minimal non-specific staining.


Assuntos
Neoplasias do Apêndice , Carcinoma Neuroendócrino , Neoplasias Intestinais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Tumores Neuroendócrinos/patologia , Biomarcadores Tumorais/metabolismo , Cromograninas , Peptídeo YY , Serotonina , Proteínas Repressoras/metabolismo , Sensibilidade e Especificidade , Sinaptofisina/metabolismo , Neoplasias do Apêndice/diagnóstico , Carcinoma Neuroendócrino/patologia
4.
J Neurochem ; 167(5): 680-695, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37924268

RESUMO

Membrane trafficking pathways mediate key microglial activities such as cell migration, cytokine secretion, and phagocytosis. However, the underlying molecular mechanism remains poorly understood. Previously, we found that synaptotagmin-11 (Syt11), a non-Ca2+ -binding Syt associated with Parkinson's disease (PD) and schizophrenia, inhibits cytokine release and phagocytosis in primary microglia. Here we reported the in vivo function of Syt11 in microglial immune responses using an inducible microglia-specific Syt11-conditional-knockout (cKO) mouse strain. Syt11-cKO resulted in activation of microglia and elevated mRNA levels of IL-6, TNF-α, IL-1ß, and iNOS in various brain regions under both resting state and LPS-induced acute inflammation state in adult mice. In a PD mouse model generated by microinjection of preformed α-synuclein fibrils into the striatum, a reduced number of microglia migrated toward the injection sites and an enhanced phagocytosis of α-synuclein fibrils by microglia were found in Syt11-cKO mice. To understand the molecular mechanism of Syt11 function, we identified its direct binding proteins vps10p-tail-interactor-1a (vti1a) and vti1b. The linker domain of Syt11 interacted with both proteins and a peptide derived from it competitively inhibited the interaction of Syt11 with vti1a/vti1b in vitro and in cells. Importantly, application of this peptide induced more cytokine secretion in wild-type microglia upon LPS treatment, phenocopying defects in Syt11 knockdown cells. Altogether, we propose that Syt11 inhibits microglial activation in vivo and regulates cytokine secretion through interactions with vti1a and vti1b.


Assuntos
Doença de Parkinson , alfa-Sinucleína , Animais , Camundongos , alfa-Sinucleína/metabolismo , Citocinas/metabolismo , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Doença de Parkinson/metabolismo , Fagocitose , Sinaptotagminas/genética
5.
Biol Psychiatry Glob Open Sci ; 3(4): 663-672, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37881566

RESUMO

Background: There is growing evidence that disturbances in cholesterol metabolism may be involved in major depressive disorder (MDD). However, it is not known if cholesterol metabolites present in the brain and periphery can be used to diagnose and predict an MDD patient's response to antidepressant treatment. Methods: A total of 176 subjects (85 patients with MDD and 91 healthy control subjects) were included in this study. The expression of peripheral and brain-specific oxysterols and related gene polymorphisms were investigated in all subjects. The severity of depression was measured using the 17-item Hamilton Depression Rating Scale, 16-item Quick Inventory of Depressive Symptoms-Self-Report, and Patient Health Questionnaire-9 for all patients with MDD before and after 12 weeks of antidepressant treatment. Results: Patients with MDD expressed higher plasma levels of 24(S)-hydroxycholesterol (24OHC) (mainly secreted from the brain) compared with healthy control subjects, and the higher levels of 24OHC were associated with 24OHC synthetase (CYP46A1) gene polymorphisms. In patients with MDD, an improved response to the 12-week antidepressant treatment was associated with a reduction of both 24OHC and 27OHC (mainly secreted from the peripheral system) levels relative to baseline levels. Nonresponders exhibited increased levels of oxysterols at the end of treatment compared with baseline. The superior reduction in oxysterol levels correlated with better outcomes from the antidepressant treatment. Conclusions: These data suggest a potential role for oxysterols as diagnostic and treatment response-related indicators for MDD.

6.
Front Psychiatry ; 14: 1224914, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37502809

RESUMO

Objective: Suicidality is commonly observed in patients with depressive episodes, and electroconvulsive therapy (ECT) has been found to be effective in treating these patients. However, the role of ECT in suicidality remains unclear. This study used resting-state functional magnetic resonance imaging (rs-fMRI) to explore the changes in brain function before and after ECT in depressed patients with suicidality. Methods: In total, 26 depressed patients with suicidality underwent rs-fMRI at baseline and after 8-12 sessions of ECT. In addition, 32 healthy controls (HCs) matched for age, gender, and educational level underwent rs-fMRI once. The amplitude of low-frequency fluctuations (ALFF), the fractional amplitude of low-frequency fluctuations (fALFF), and regional homogeneity (ReHo) were measured to evaluate whole brain function. Differences between the groups and time points (before and after ECT) were compared. Clinical symptoms were assessed using the 17-item Hamilton Depression Scale (HAMD-17) and Beck Scale for Suicide Ideation (BSSI). Results: At baseline, patients exhibited decreased ALFF in the right postcentral and precentral gyrus and decreased fALFF in the right supramarginal and postcentral gyrus, left superior frontal gyrus (SFG), as well as the superior and middle temporal gyrus compared to HCs. Patients also had lower ReHo in the left amygdala, anterior cingulate, and postcentral gyrus, and in the right thalamus, insula, and postcentral gyrus. They also exhibited higher ALFF in the bilateral temporal gyrus and insula as well as higher fALFF in the cerebellum. Following ECT, fALFF in the left SFG and orbital frontal cortex (OFC) significantly increased and was inversely correlated with the reduction of BSSI scores (r = -0.416, p = 0.048), whereas no correlation was found with changes in HAMD-17scores. Conclusion: Our findings suggest that the left SFG and OFC may play a key role in the mechanism of ECT for suicidality. The decrease of fALFF in the left SFG and OFC may represent a potential mechanism through which ECT effectively treats suicidality in depressed patients.

7.
BMC Psychiatry ; 23(1): 449, 2023 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-37340368

RESUMO

BACKGROUND: Bipolar disorder (BD) is characterized by intensive mood fluctuations. While hormones imbalance plays important role in the mood swings, it is unknown whether peripheral hormones profiles could differentiate the manic and depressive mood episodes in BD. In this study, we investigated the changes of various hormones and inflammatory markers across distinct mood episodes of BD in a large clinical study to provide mood episode-specific peripheral biomarkers for BD. METHODS: A total of 8332 BD patients (n = 2679 depressive episode; n = 5653 manic episode) were included. All patients were in acute state of mood episodes and need hospitalization. A panel of blood tests were performed for levels of sex hormones (serum levels of testosterone, estradiol, and progesterone), stress hormones (adrenocorticotropic hormone and cortisol), and an inflammation marker (C-reactive protein, CRP). A receiver operating characteristic (ROC) curve was used to analyze the discriminatory potential of the biomarkers for mood episodes. RESULTS: In overall comparison between mood episodes, the BD patients expressed higher levels of testosterone, estradiol, progesterone, and CRP (P < 0.001) and lower adrenocorticotropic hormone (ACTH) level (P < 0.001) during manic episode. The episode-specific changes of testosterone, ACTH, and CRP levels remained between the two groups (P < 0.001) after correction for the confounding factors including age, sex, BMI, occupation, marital status, tobacco use, alcohol consumption, psychotic symptoms, and age at onset. Furthermore, we found a sex- and age-specific impact of combined biomarkers in mood episodes in male BD patients aged ≥ 45 years (AUC = 0.70, 95% CI, 0.634-0.747), not in females. CONCLUSIONS: While both hormone and inflammatory change is independently associated with mood episodes, we found that the combination of sex hormones, stress hormones and CRP could be more effective to differentiate the manic and depressive episode. The biological signatures of mood episodes in BD patients may be sex- and age-specific. Our findings not only provide mood episode-related biological markers, but also better support for targeted intervention in BD treatments.


Assuntos
Transtorno Bipolar , Feminino , Humanos , Masculino , Mania/complicações , Progesterona , Hidrocortisona , Biomarcadores , Hormônio Adrenocorticotrópico , Testosterona , Estradiol
9.
J Clin Invest ; 132(17)2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35834335

RESUMO

Solid organ transplantation is the preferred treatment for end-stage organ failure. Although transplant recipients take life-long immunosuppressive drugs, a substantial percentage of them still reject their allografts. Strikingly, barrier organs colonized with microbiota have significantly shorter half-lives than non-barrier transplanted organs, even in immunosuppressed hosts. We previously demonstrated that skin allografts monocolonized with the common human commensal Staphylococcus epidermidis (S.epi) are rejected faster than germ-free (GF) allografts in mice because the presence of S.epi augments the effector alloimmune response locally in the graft. Here, we tested whether host immune responses against graft-resident commensal microbes, including S.epi, can damage colonized grafts independently from the alloresponse. Naive hosts mounted an anticommensal T cell response to colonized, but not GF, syngeneic skin grafts. Whereas naive antigraft commensal T cells modestly damaged colonized syngeneic skin grafts, hosts with prior anticommensal T cell memory mounted a post-transplant immune response against graft-resident commensals that significantly damaged colonized, syngeneic skin grafts. Importantly, allograft recipients harboring this host-versus-commensal immune response resisted immunosuppression. The dual effects of host-versus-commensal and host-versus-allograft responses may partially explain why colonized organs have poorer outcomes than sterile organs in the clinic.


Assuntos
Rejeição de Enxerto , Transplante de Órgãos , Animais , Humanos , Imunidade , Camundongos , Transplante de Pele , Transplante Homólogo
10.
Am J Transplant ; 22(10): 2348-2359, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35633180

RESUMO

Oral antigen exposure is a powerful, non-invasive route to induce immune tolerance to dietary antigens, and has been modestly successful at prolonging graft survival in rodent models of transplantation. To harness the mechanisms of oral tolerance for promoting long-term graft acceptance, we developed a mouse model where the antigen ovalbumin (OVA) was introduced orally prior to transplantation with skin grafts expressing OVA. Oral OVA treatment pre-transplantation promoted permanent graft acceptance and linked tolerance to skin grafts expressing OVA fused to the additional antigen 2W. Tolerance was donor-specific, as secondary donor-matched, but not third-party allografts were spontaneously accepted. Oral OVA treatment promoted an anergic phenotype in OVA-reactive CD4+ and CD8+ conventional T cells (Tconvs) and expanded OVA-reactive Tregs pre-transplantation. However, skin graft acceptance following oral OVA resisted partial depletion of Tregs and blockade of PD-L1. Mechanistically, we revealed a role for the proximal gut draining lymph nodes (gdLNs) in mediating this effect, as an intestinal infection that drains to the proximal gdLNs prevented tolerance induction. Our study extends previous work applying oral antigen exposure to transplantation and serves as proof of concept that the systemic immune mechanisms supporting oral tolerance are sufficient to promote long-term graft acceptance.


Assuntos
Isoantígenos , Transplante de Pele , Animais , Antígenos , Antígeno B7-H1 , Sobrevivência de Enxerto , Tolerância Imunológica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ovalbumina , Tolerância ao Transplante
11.
Circ Res ; 130(9): 1321-1341, 2022 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-35382554

RESUMO

BACKGROUND: Cerebral small vessel injury, including loss of endothelial tight junctions, endothelial dysfunction, and blood-brain barrier breakdown, is an early and typical pathology for Alzheimer's disease, cerebral amyloid angiopathy, and hypertension-related cerebral small vessel disease. Whether there is a common mechanism contributing to these cerebrovascular alterations remains unclear. Studies have shown an elevation of BACE1 (ß-site amyloid precursor protein cleaving enzyme 1) in cerebral vessels from cerebral amyloid angiopathy or Alzheimer's disease patients, suggesting that vascular BACE1 may involve in cerebral small vessel injury. METHODS: To understand the contribution of vascular BACE1 to cerebrovascular impairments, we combined cellular and molecular techniques, mass spectrometry, immunostaining approaches, and functional testing to elucidate the potential pathological mechanisms. RESULTS: We observe a 3.71-fold increase in BACE1 expression in the cerebral microvessels from patients with hypertension. Importantly, we discover that an endothelial tight junction protein, occludin, is a completely new substrate for endothelial BACE1. BACE1 cleaves occludin with full-length occludin reductions and occludin fragment productions. An excessive cleavage by elevated BACE1 induces membranal accumulation of caveolin-1 and subsequent caveolin-1-mediated endocytosis, resulting in lysosomal degradation of other tight junction proteins. Meanwhile, membranal caveolin-1 increases the binding to eNOS (endothelial nitric oxide synthase), together with raised circulating Aß (ß-amyloid peptides) produced by elevated BACE1, leading to an attenuation of eNOS activity and resultant endothelial dysfunction. Furthermore, the initial endothelial damage provokes chronic reduction of cerebral blood flow, blood-brain barrier leakage, microbleeds, tau hyperphosphorylation, synaptic loss, and cognitive impairment in endothelial-specific BACE1 transgenic mice. Conversely, inhibition of aberrant BACE1 activity ameliorates tight junction loss, endothelial dysfunction, and memory deficits. CONCLUSIONS: Our findings establish a novel and direct relationship between endothelial BACE1 and cerebral small vessel damage, indicating that abnormal elevation of endothelial BACE1 is a new mechanism for cerebral small vessel disease pathogenesis.


Assuntos
Doença de Alzheimer , Angiopatia Amiloide Cerebral , Doenças de Pequenos Vasos Cerebrais , Hipertensão , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide , Animais , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Caveolina 1/genética , Caveolina 1/metabolismo , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/metabolismo , Humanos , Hipertensão/complicações , Camundongos , Camundongos Transgênicos , Óxido Nítrico Sintase Tipo III/metabolismo , Ocludina/metabolismo , Proteínas de Junções Íntimas , Junções Íntimas/metabolismo
12.
Mol Neurobiol ; 59(1): 405-419, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34705229

RESUMO

The cell-to-cell transmission of pathological α-synuclein (α-syn) has been proposed to be a critical event in the development of synucleinopathies. Recent studies have begun to reveal the underlying molecular mechanism of α-syn propagation. As one of the central steps, α-syn secretion is reported to be Ca2+-dependent and mediated by unconventional exocytosis. However, the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) requirement and vesicle identity of α-syn secretion remain elusive. Here we found that α-syn secretion is SNARE-dependent by systematically knocking down Q-SNAREs and R-SNAREs in exocytosis pathways. α-Syn secretion was mainly mediated by syntaxin 4 (STX4) and synaptosomal-associated protein 23 (SNAP23), but did not require STX1 and SNAP25, in differentiated SH-SY5Y cells. On the other hand, vesicle-associated membrane protein 3 (VAMP3), VAMP7, and VAMP8 were all involved in α-syn secretion, most likely in overlapping pathways. Application of super-resolution microscopy revealed localization of both endogenous and overexpressed α-syn in endosomes, lysosomes, and autophagosomes in rat primary cortical neurons. α-Syn co-localized with microtubule-associated protein 1 light chain 3 (LC3) most extensively, suggesting its tight association with the autophagy pathway. Consistently, α-syn secretion was regulated by the autophagy-lysosome pathway. Collectively, our data suggest that α-syn secretion is SNARE-dependent and is mediated by multiple vesicular pathways including exocytosis of recycling endosomes, multivesicular bodies, autophagosomes, and lysosomes.


Assuntos
Exocitose/fisiologia , Neurônios/metabolismo , Proteínas SNARE/metabolismo , Proteínas de Transporte Vesicular/metabolismo , alfa-Sinucleína/metabolismo , Animais , Autofagossomos/metabolismo , Linhagem Celular Tumoral , Endossomos/metabolismo , Humanos , Lisossomos/metabolismo , Ratos , Ratos Sprague-Dawley
13.
J Neurosci ; 42(6): 1154-1165, 2022 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-34903570

RESUMO

Women have a higher prevalence and incidence of Alzheimer's disease (AD) than age-matched men, and loss of estrogen might be partially responsible for the higher risk of AD in aged women. While ß-secretase (BACE1) plays an important role in AD pathogenesis, whether BACE1 involved the sex difference in AD pathology remains unclear. This study investigated the hypothesis that estrogen regulates BACE1 transcription via the estrogen response element (ERE) and designated pathways. Using estrogen receptor (ER) knock-out mice and mutagenesis of EREs in HEK293 cells, we demonstrated sex-specific inhibition of BACE1 transcription by estrogen via direct binding to ERE sites and ERα. We also used a repressor of estrogen receptor activity (REA) and showed that an REA-ERE complex downregulated BACE1. A chromatin immunoprecipitation assay analysis determined that all three EREs at the BACE1 promoter were required for estradiol-mediated downregulation of BACE1 transcription in mice. Last, we confirmed the impairment of the REA pathway in the cortex of female AD patients. Our study identified an estrogen-specific BACE1 transcriptional regulation pathway from cell and animal models to AD patients.SIGNIFICANCE STATEMENT With the increase in the aging population and Alzheimer's disease worldwide, an urgent need to find effective approaches to treat or prevent AD. Women have a higher prevalence and incidence of AD than men. Identification of the sex-specific risk for AD may be valuable for disease prevention. This study evaluated several estrogen response element (ERE) sites on the promoter of ß-secretase (BACE1), a key enzyme for AD pathology. We demonstrated that estrogen downregulated BACE1 transcription through direct binding and complex formation with ERE and cofactors. Our novel findings provide evidence that an estrogen supplement may decrease the risk of AD in menopausal and postmenopausal women. Furthermore, this study demonstrates the "sex-specific" mechanisms of BACE1 as a role in AD pathogenesis.


Assuntos
Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/biossíntese , Estrogênios/metabolismo , Regulação da Expressão Gênica/fisiologia , Animais , Receptor alfa de Estrogênio/metabolismo , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Knockout , Elementos de Resposta/fisiologia , Caracteres Sexuais , Transcrição Gênica
14.
Front Psychiatry ; 12: 682691, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34721095

RESUMO

Background: Recent literature suggests that α-Klotho, a widely recognized anti-aging protein, is involved in longevity as well as in many diseases, including Alzheimer's disease, and depression. Although the Klotho gene encodes α-Klotho, a single transmembrane protein with intracellular and extracellular domains, the relationship between Klotho gene polymorphism and circulating α-Klotho levels in patients with major depressive disorder (MDD) is not clear. Methods: A total of 144 MDD patients and 112 age-matched healthy controls were included in this study. The Klotho genetic polymorphisms (rs9536314, rs9527025, and rs9315202) and plasma α-Klotho levels were measured by PCR and ELISA, respectively. The severity of depressive symptoms was estimated using the Hamilton Depression Scale (HAMD). Results: We found a significantly lower level of plasma α-Klotho in the MDD patients than in controls. Among them, only elderly MDD patients (first episode) showed significantly lower α-Klotho levels than the age-matched controls, while elderly recurrent and young MDD patients showed no difference in plasma α-Klotho levels from age-matched controls. The young MDD group showed a significantly earlier onset age, higher plasma α-Klotho levels, and lower HAMD scores than those in the elderly MDD group. While the plasma α-Klotho levels were higher in rs9315202 T alleles carrier regardless age or sex, the rs9315202 T allele was negatively correlated with disease severity only in the elderly MDD patients. Conclusion: The results of our study showed that only elderly MDD patients showed a decrease in plasma α-Klotho levels along with an increase in disease severity as well as an association with the number of rs9315202 T alleles, and not young MDD patients compared to age-matched controls. Our data suggest that circulating α-Klotho levels combined with Klotho genetic polymorphisms are important in elderly MDD patients, particularly carriers of the Klotho gene rs9315202 T allele.

15.
Behav Neurol ; 2021: 5346507, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34594430

RESUMO

Epidemiological studies have suggested that traumatic stress increases vulnerability to various mental disorders, such as dementia and psychiatric disorders. While women are more vulnerable than men to depression and anxiety, it is unclear whether endogenous estrogens are responsible for the underlying sex-specific mechanisms. In this study, the aromatase gene heterozygous (Ar+/-) mice were used as an endogenous estrogen deficiency model and age- and sex-matched wild type mice (WT) as controls to study the predator odor 2,3,5-trimethyl-3-thiazoline- (TMT-) induced short- and long-term cognitive and social behavior impairments. In addition, the changes in brain regional neurotransmitters and their associations with TMT-induced changes in behaviors were further investigated in these animals. Our results showed TMT induced immediate fear response in both Ar+/- and WT mice regardless of sexes. TMT induced an acute impairment of novel object recognition memory and long-term social behavior impairment in WT mice, particularly in females, while Ar+/- mice showed impaired novel object recognition in both sexes and TMT-elevated social behaviors, particularly in males. TMT failed to induce changes in the prepulse inhibition (PPI) test in both groups. TMT resulted in a slight increase of DOPAC/DA ratio in the cortex and a significant elevation of this ratio in the striatum of WT mice. In addition, the ratio of HIAA/5-HT was significantly elevated in the cortex of TMT-treated WT mice, which was not found in TMT-treated Ar+/- mice. Taken together, our results indicate that TMT exposure can cause cognitive and social behavior impairments as well as change catecholamine metabolism in WT mice, and endogenous estrogen deficiency might desensitize the behavioral and neurochemical responses to TMT in Ar+/- mice.


Assuntos
Medo , Odorantes , Animais , Aromatase/genética , Comportamento Animal , Cognição , Estrogênios , Feminino , Humanos , Masculino , Camundongos , Comportamento Social
16.
J Neurochem ; 159(4): 729-741, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34599505

RESUMO

Recent work has revealed that spontaneous release plays critical roles in the central nervous system, but how it is regulated remains elusive. Here, we report that synaptotagmin-11 (Syt11), a Ca2+ -independent Syt isoform associated with schizophrenia and Parkinson's disease, suppressed spontaneous release. Syt11-knockout hippocampal neurons showed an increased frequency of miniature excitatory post-synaptic currents while over-expression of Syt11 inversely decreased the frequency. Neither knockout nor over-expression of Syt11 affected the average amplitude, suggesting the pre-synaptic regulation of spontaneous neurotransmission by Syt11. Glutathione S-transferase pull-down, co-immunoprecipitation, and affinity-purification experiments demonstrated a direct interaction of Syt11 with vps10p-tail-interactor-1a (vti1a), a non-canonical SNARE protein that maintains spontaneous release. Importantly, knockdown of vti1a reversed the phenotype of Syt11 knockout, identifying vti1a as the main target of Syt11 inhibition. Domain analysis revealed that the C2A domain of Syt11 bound vti1a with high affinity. Consistently, expression of the C2A domain alone rescued the phenotype of elevated spontaneous release in Syt11-knockout neurons similar to the full-length protein. Altogether, our results suggest that Syt11 inhibits vti1a-containing vesicles during spontaneous release.


Assuntos
Proteínas Qb-SNARE/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Sinaptotagminas/farmacologia , Animais , Fenômenos Eletrofisiológicos , Potenciais Pós-Sinápticos Excitadores , Técnicas de Introdução de Genes , Hipocampo/patologia , Imunoprecipitação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/patologia , Cultura Primária de Células
17.
Front Psychiatry ; 12: 711734, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34408685

RESUMO

Accumulating evidence from clinical, genetic, and epidemiologic studies suggest that schizophrenia might be a neuronal development disorder. While oxysterols are important factors in neurodevelopment, it is unknown whether oxysterols might be involved in development of schizophrenia. The present study investigated the relationship between tissue-specifically originated oxysterols and risk of schizophrenia. A total of 216 individuals were recruited in this study, including 76 schizophrenia patients, 39 clinical high-risk (CHR) subjects, and 101 healthy controls (HC). We investigated the circulating levels of brain-specific oxysterol 24(S)-hydroxycholesterol (24OHC) and peripheral oxysterol 27-hydroxycholesterol (27OHC) in all participants and analyzed the potential links between the oxysterols and specific clinical symptoms in schizophrenic patients and CHR. Our data showed an elevation of 24OHC in both schizophrenia patients and CHR than that in HC, while a lower level of 27OHC in the schizophrenia group only. The ratio of 24OHC to 27OHC was only increased in the schizophrenic group compared with CHR and HC. For the schizophrenic patients, the circulating 24OHC levels are significantly associated with disease duration, positively correlated with the positive and negative syndrome total scores, while the 27OHC levels were inversely correlated with the positive symptom scores. Together, our data demonstrated the disruption of tissue-specifically originated cholesterol metabolism in schizophrenia and CHR, suggesting the circulating 24OHC or 24OHC/27OHC ratio might not only be a potential indicator for risk for schizophrenia but also be biomarkers for functional abnormalities in neuropathology of schizophrenia.

18.
Mol Neurobiol ; 58(6): 2874-2885, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33527303

RESUMO

α-Klotho is known for its aging-related functions and is associated with neurodegenerative diseases, accelerated aging, premature morbidity, and mortality. Recent literature suggests that α-Klotho is also involved in the regulation of mental functions, such as cognition and psychosis. While most of studies of α-Klotho are focusing on its anti-aging functions and protective role in dementia, increasing evidence showed many shared symptoms between depression and dementia, while depression has been proposed as the preclinical stage of dementia such as Alzheimer's disease (AD). To see whether and how α-Klotho can be a key biological link between depression and dementia, in this review, we first gathered the evidence on biological distribution and function of α-Klotho in psychiatric functions from animal studies to human clinical investigations with a focus on the regulation of cognition and mood. Then, we discussed and highlighted the potential common underlying mechanisms of α-Klotho between psychiatric diseases and cognitive impairment. Finally, we hypothesized that α-Klotho might serve as a neurobiological link between depression and dementia through the regulation of oxidative stress and inflammation.


Assuntos
Demência/metabolismo , Depressão/metabolismo , Glucuronidase/metabolismo , Idoso , Envelhecimento/metabolismo , Animais , Disfunção Cognitiva/metabolismo , Humanos , Proteínas Klotho , Estresse Oxidativo
19.
J Alzheimers Dis ; 80(1): 407-419, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33554907

RESUMO

BACKGROUND: The choroid is involved directly or indirectly in many pathological conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). OBJECTIVE: The objective of this study was to investigate the association between retinal choroidal properties and the pathology of AD by determining choroidal thickness, hippocampus volume, cognitive functions, and plasma BACE1 activity. METHODS: In this cross-sectional study, 37 patients with AD and 34 age-matched controls were included. Retinal choroidal thickness was measured via enhanced depth imaging optical coherence tomography. Hippocampal volume was measured via 3.0T MRI. Cognitive functions were evaluated using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog). Plasma BACE1 activity was analyzed using a fluorescence substrate-based plasma assay, and regression model were to analyze the data. RESULTS: Retinal choroidal thickness was significantly thinner in the AD group than in the control group [(114.81±81.30) µm versus (233.79±38.29) µm, p < 0.05]. Multivariable regression analysis indicated that the ADAS-cog scores (ß=-0.772, p = 0.000) and age (ß=-0.176, p = 0.015) were independently associated with choroidal thickness. The logistic regression model revealed that the subfoveal choroidal thickness was a significant predictor for AD (OR = 0.984, 95% CI: 0.972-0.997). CONCLUSION: There was a general tendency of choroid thinning as the cognitive function declined. Although choroidal thickness was not a potential indicator for early stage AD, it was valuable in monitoring AD progression.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Corioide/diagnóstico por imagem , Retina/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Secretases da Proteína Precursora do Amiloide/sangue , Ácido Aspártico Endopeptidases/sangue , Cognição , Estudos Transversais , Feminino , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Testes Neuropsicológicos , Desempenho Psicomotor , Tomografia de Coerência Óptica
20.
Neurosci Lett ; 739: 135402, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-32976921

RESUMO

Synaptotagmin-11 (Syt11) is associated with schizophrenia and Parkinson's disease (PD) and is a critical substrate of parkin, an E3 ubiquitin ligase linked to PD. Previously we reported that Syt11 regulates multiple membrane trafficking pathways in neurons and glia. However, the regulation of Syt11 degradation remains largely unknown. As the ubiquitin-proteasome pathway (UPP) plays crucial roles in protein degradation and quality control, we investigated UPP-dependent Syt11 degradation in this study. We found that Syt11 is a short-lived protein with a half-life of 1.49 h in the presence of a protein synthesis inhibitor cycloheximide and is mainly degraded by UPP in neurons. The degradation was further accelerated under sustained neuronal activity and was parkin-dependent. Interestingly, Syt11 had a faster turnover in astrocytes with a half-life of 0.58 h, and UPP partially contributed to its degradation. Mechanical stress applied on astrocytes by hypoosmotic treatment led to reduced Syt11 protein level but increased parkin level. However, the degradation of Syt11 was parkin-independent under both isoosmotic and hypoosmotic condition. Altogether, our results revealed active and distinct proteolytic regulation of Syt11 in neurons and astrocytes.


Assuntos
Astrócitos/metabolismo , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Proteólise , Sinaptotagminas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Feminino , Masculino , Camundongos , Cultura Primária de Células , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitinação
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