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1.
Biochimie ; 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32061804

RESUMO

Neural tube defects (NTDs) are a broad class of congenital birth defects that result from the failure of neural tube closure during neurulation. Folic acid supplementation has been shown to prevent the occurrence of NTDs by as much as 70% in some human populations, and folate deficiency in a pregnant woman is associated with increased risk for having an NTD affected infant. Thus, folate transport-related genes and genes involved in the subsequent folate-mediated one carbon metabolic pathway have long been considered primary candidates to study the genetic etiology of human NTDs. Herein, we review the genes involved in folate transport and one carbon metabolism thus far identified as contributing variants that influence human NTD risk, and place these findings in the context of our evolving understanding of the complex genetic architecture underlying these defects.

2.
Nat Commun ; 11(1): 319, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949159

RESUMO

Optimal functioning of neuronal networks is critical to the complex cognitive processes of memory and executive function that deteriorate in Alzheimer's disease (AD). Here we use cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional. We introduce the term protein connectivity-based dysfunction (PCBD) to define this mechanism. Among most sensitive to PCBD are pathways with key roles in synaptic plasticity. We show at cellular and target organ levels that network connectivity and functional imbalances revert to normal levels upon epichaperome inhibition. In conclusion, we provide proof-of-principle to propose AD is a PCBDopathy, a disease of proteome-wide connectivity defects mediated by maladaptive epichaperomes.

3.
Hum Mutat ; 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31898828

RESUMO

DNA damage response (DDR) genes orchestrating the network of DNA repair, cell cycle control, are essential for the rapid proliferation of neural progenitor cells. To date, the potential association between specific DDR genes and the risk of human neural tube defects (NTDs) has not been investigated. Using whole-genome sequencing and targeted sequencing, we identified significant enrichment of rare deleterious RAD9B variants in spina bifida cases compared to controls (8/409 vs. 0/298; p = .0241). Among the eight identified variants, the two frameshift mutants and p.Gln146Glu affected RAD9B nuclear localization. The two frameshift mutants also decreased the protein level of RAD9B. p.Ser354Gly, as well as the two frameshifts, affected the cell proliferation rate. Finally, p.Ser354Gly, p.Ser10Gly, p.Ile112Met, p.Gln146Glu, and the two frameshift variants showed a decreased ability for activating JNK phosphorylation. RAD9B knockdowns in human embryonic stem cells profoundly affected early differentiation through impairing PAX6 and OCT4 expression. RAD9B deficiency impeded in vitro formation of neural organoids, a 3D cell culture model for human neural development. Furthermore, the RNA-seq data revealed that loss of RAD9B dysregulates cell adhesion genes during organoid formation. These results represent the first demonstration of a DDR gene as an NTD risk factor in humans.

4.
J Pediatr Surg ; 2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31301886

RESUMO

BACKGROUND/PURPOSE: In 2004, a heritable occurrence of spina bifida was reported in sheep on a farm in the United States. We maintained and characterized the spina bifida phenotype in this flock to assess its potential as an alternative surgical model. METHODS: A breeding strategy was developed in which the sheep were crossed to maintain or increase the occurrence of spina bifida. Measurements and observations were recorded regarding lesion size, birthweight, ambulatory capacity, or urological function, and necropsies were performed on spina bifida afflicted lambs in conjunction with magnetic resonance imaging to determine the character of the spina bifida defects and assess the presence of Chiari-like malformations or hydrocephalus. RESULTS: The defects were observed to be more prevalent in ram lambs, and the rate of spina bifida per litter could be increased through backcrossing or by selection of a productive ewe breed. The lambs displayed a range of ambulatory and urological deficits which could be used to evaluate new fetal repair methodologies. Finally, affected lambs were shown to demonstrate severe Chiari malformations and hydrocephalus. CONCLUSIONS: We have determined that use of these sheep as a natural source for spina bifida fetuses is feasible and could supplement the deficits of current sheep models for myelomeningocele repair. LEVEL OF EVIDENCE: Level IV.

5.
AIDS ; 33(13): 1967-1976, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31259764

RESUMO

OBJECTIVE: Maternal folate (vitamin B9) status is the largest known modifier of neural tube defect risk, so we evaluated folate-related mechanisms of action for dolutegravir (DTG) developmental toxicity. DESIGN: Folate receptor 1 (FOLR1) was examined as a target for DTG developmental toxicity using protein and cellular interaction studies and an animal model. METHODS: FOLR1 competitive binding studies were used to test DTG for FOLR1 antagonism. Human placenta cell line studies were used to test interactions with DTG, folate, and cations. Zebrafish were selected as an animal model to examine DTG-induced developmental toxicity and rescue strategies. RESULTS: FOLR1 binding studies indicate DTG is a noncompetitive FOLR1 antagonist at therapeutic concentrations. In-vitro testing indicates calcium (2 mmol/l) increases FOLR1-folate interactions and alters DTG-FOLR1-folate interactions and cytotoxicity. DTG does not inhibit downstream folate metabolism by dihydrofolate reductase. Early embryonic exposure to DTG is developmentally toxic in zebrafish, and supplemental folic acid can mitigate DTG developmental toxicity. CONCLUSION: Folates and FOLR1 are established modifiers of risk for neural tube defects, and binding data indicates DTG is a partial antagonist of FOLR1. Supplemental folate can ameliorate increased developmental toxicity due to DTG in zebrafish. The results from these studies are expected to inform and guide future animal models and clinical studies of DTG-based antiretroviral therapy in women of childbearing age.

6.
Brain Res ; 1656: 63-67, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-26972536

RESUMO

Data generated in Niemann Pick type C1 (NPC1) human embryonic and human induced pluripotent stem cell derived neurons complement on-going studies in animal models and provide the first example, in disease-relevant human cells, of processes that underlie preferential neuronal defects in a NPC1. Our work and that of other investigators in human neurons derived from stem cells highlight the importance of performing rigorous mechanistic studies in relevant cell types to guide drug discovery and therapeutic development, alongside of existing animal models. Through the use of human stem cell-derived models of disease, we can identify and discover or repurpose drugs that revert early events that lead to neuronal failure in NPC1. Together with the study of disease pathogenesis and efficacy of therapies in animal models, these strategies will fulfill the promise of stem cell technology in the development of new treatments for human diseases. This article is part of a Special Issue entitled SI: Exploiting human neurons.


Assuntos
Células-Tronco Embrionárias/fisiologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Doença de Niemann-Pick Tipo C/fisiopatologia , Animais , Descoberta de Drogas , Células-Tronco Embrionárias/efeitos dos fármacos , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Doença de Niemann-Pick Tipo C/tratamento farmacológico
7.
Neurol Neuroimmunol Neuroinflamm ; 3(3): e237, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27218118

RESUMO

BACKGROUND: Recent studies have implicated specific assembly subtypes of ß-amyloid (Aß) peptide, specifically soluble oligomers (soAß) as disease-relevant structures that may underlie memory loss in Alzheimer disease. Removing existing soluble and insoluble Aß assemblies is thought to be essential for any attempt at stabilizing brain function and slowing cognitive decline in Alzheimer disease. IV immunoglobulin (IVIg) therapies have been shown to contain naturally occurring polyclonal antibodies that recognize conformational neoepitopes of soluble or insoluble Aß assemblies including soAß. These naturally occurring polyclonal antibodies have been suggested to underlie the apparent clinical benefits of IVIg. However, direct evidence linking anti-Aß antibodies to the clinical bioactivity of IVIg has been lacking. METHODS: Five-month-old female Dutch APP E693Q mice were treated for 3 months with neat IVIg or with IVIg that had been affinity-depleted over immobilized Aß conformers in 1 of 2 assembly states. Memory was assessed in a battery of tests followed by quantification of brain soAß levels using standard anti-soAß antibodies. RESULTS: We provide evidence that NU4-type soAß (NU4-soAß) assemblies accumulate in the brains of Dutch APP E693Q mice and are associated with defects in memory, even in the absence of insoluble Aß plaques. Memory benefits were associated with depletion from APP E693Q mouse brain of NU4-soAß and A11-soAß but not OC-type fibrillar Aß oligomers. CONCLUSIONS: We propose that targeting of specific soAß assembly subtypes may be an important consideration in the therapeutic and/or prophylactic benefit of anti-Aß antibody drugs.

8.
Sci Rep ; 5: 17042, 2015 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-26608390

RESUMO

The presenilin 1 (PSEN1) L271V mutation causes early-onset familial Alzheimer's disease by disrupting the alternative splicing of the PSEN1 gene, producing some transcripts harboring the L271V point mutation and other transcripts lacking exon 8 (PS1(∆exon8)). We previously reported that PS1 L271V increased amyloid beta (Aß) 42/40 ratios, while PS1(∆exon8) reduced Aß42/40 ratios, indicating that the former and not the exon 8 deletion transcript is amyloidogenic. Also, PS1(∆exon8) did not rescue Aß generation in PS1/2 double knockout cells indicating its identity as a severe loss-of-function splice form. PS1(∆exon8) is generated physiologically raising the possibility that we had identified the first physiological inactive PS1 isoform. We studied PS1(∆exon8) in vivo by crossing PS1(∆exon8) transgenics with either PS1-null or Dutch APP(E693Q) mice. As a control, we crossed APP(E693Q) with mice expressing a deletion in an adjacent exon (PS1(∆exon9)). PS1(∆exon8) did not rescue embryonic lethality or Notch-deficient phenotypes of PS1-null mice displaying severe loss of function in vivo. We also demonstrate that this splice form can interact with wildtype PS1 using cultured cells and co-immunoprecipitation (co-IP)/bimolecular fluorescence complementation. Further co-IP demonstrates that PS1(∆exon8) interacts with nicastrin, participating in the γ-secretase complex formation. These data support that catalytically inactive PS1(∆exon8) is generated physiologically and participates in protein-protein interactions.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Éxons/genética , Glicoproteínas de Membrana/metabolismo , Presenilina-1/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Animais , Encéfalo/metabolismo , Embrião de Mamíferos/metabolismo , Retículo Endoplasmático/metabolismo , Fluorescência , Células HEK293 , Humanos , Imunoprecipitação , Camundongos Knockout , Atividade Motora , Fenótipo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Presenilina-1/deficiência , Presenilina-1/metabolismo , Ligação Proteica , Deleção de Sequência/genética , Transgenes
9.
PLoS One ; 9(3): e92750, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24671215

RESUMO

BACKGROUND AND PURPOSE: In this study, we demonstrate the use of Molecular topology (MT) in an Alzheimer's disease (AD) drug discovery program. MT uses and expands upon the principles governing the molecular connectivity theory of numerically characterizing molecular structures, in the present case, active anti-AD drugs/agents, using topological descriptors to build models. Topological characterization has been shown to embody sufficient molecular information to provide strong correlation to therapeutic efficacy. EXPERIMENTAL APPROACH: We used MT to include multiple bioactive properties that allows for the identification of multi-functional single agent compounds, in this case, the dual functions of ß-amyloid (Aß) -lowering and anti-oligomerization. Using this technology, we identified and designed novel compounds in chemical classes unrelated to current anti-AD agents that exert dual Aß lowering and anti-Aß oligomerization activities in animal models of AD. AD is a multifaceted disease with different pathological features. CONCLUSION AND IMPLICATIONS: Our study, for the first time, demonstrated that MT can provide novel strategy for discovering drugs with Aß lowering and anti-aggregation dual activities for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/química , Descoberta de Drogas , Agregados Proteicos , Animais , Bases de Dados como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Estudos de Viabilidade , Feminino , Humanos , Camundongos Transgênicos , Modelos Moleculares , Multimerização Proteica , Resultado do Tratamento
10.
11.
J Comp Neurol ; 522(10): 2319-35, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24415002

RESUMO

Alzheimer's disease (AD) is a complex and slowly progressing dementing disorder that results in neuronal and synaptic loss, deposition in brain of aberrantly folded proteins, and impairment of spatial and episodic memory. Most studies of mouse models of AD have employed analyses of cognitive status and assessment of amyloid burden, gliosis, and molecular pathology during disease progression. Here we sought to understand the behavioral, cellular, ultrastructural, and molecular changes that occur at a pathological stage equivalent to the early stages of human AD. We studied the TgCRND8 mouse, a model of aggressive AD amyloidosis, at an early stage of plaque pathology (3 months of age) in comparison to their wildtype littermates and assessed changes in cognition, neuron and spine structure, and expression of synaptic glutamate receptor proteins. We found that, at this age, TgCRND8 mice display substantial plaque deposition in the neocortex and hippocampus and impairment on cued and contextual memory tasks. Of particular interest, we also observed a significant decrease in the number of neurons in the hippocampus. Furthermore, analysis of CA1 neurons revealed significant changes in apical and basal dendritic spine types, as well as altered expression of GluN1 and GluA2 receptors. This change in molecular architecture within the hippocampus may reflect a rising representation of inherently less stable thin spine populations, which can cause cognitive decline. These changes, taken together with toxic insults from amyloid-ß protein, may underlie the observed neuronal loss.


Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Medo , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Plasticidade Neuronal/fisiologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Amiloidose/metabolismo , Amiloidose/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Contagem de Células , Sinais (Psicologia) , Dendritos/metabolismo , Dendritos/patologia , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Placa Amiloide/metabolismo , Placa Amiloide/patologia
12.
PLoS One ; 9(1): e84547, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24416243

RESUMO

Presenilin 1 (PSEN1) encodes the catalytic subunit of γ-secretase, and PSEN1 mutations are the most common cause of early onset familial Alzheimer's disease (FAD). In order to elucidate pathways downstream of PSEN1, we characterized neural progenitor cells (NPCs) derived from FAD mutant PSEN1 subjects. Thus, we generated induced pluripotent stem cells (iPSCs) from affected and unaffected individuals from two families carrying PSEN1 mutations. PSEN1 mutant fibroblasts, and NPCs produced greater ratios of Aß42 to Aß40 relative to their control counterparts, with the elevated ratio even more apparent in PSEN1 NPCs than in fibroblasts. Molecular profiling identified 14 genes differentially-regulated in PSEN1 NPCs relative to control NPCs. Five of these targets showed differential expression in late onset AD/Intermediate AD pathology brains. Therefore, in our PSEN1 iPSC model, we have reconstituted an essential feature in the molecular pathogenesis of FAD, increased generation of Aß42/40, and have characterized novel expression changes.


Assuntos
Doença de Alzheimer/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Neurais/metabolismo , Presenilina-1/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Peptídeos beta-Amiloides/biossíntese , Animais , Apolipoproteínas E/genética , Sequência de Bases , Encéfalo/citologia , Encéfalo/patologia , Diferenciação Celular , Linhagem Celular , Proteínas do Olho/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Genótipo , Humanos , Mutação , Proteínas do Tecido Nervoso/genética , Neurônios/citologia , Neurônios/patologia , Fragmentos de Peptídeos/biossíntese , Presenilina-1/genética , Ratos , Proteínas Supressoras da Sinalização de Citocina/genética
13.
J Neurosci ; 33(16): 7099-107, 2013 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-23595767

RESUMO

Endosomal sorting of the Alzheimer amyloid precursor protein (APP) plays a key role in the biogenesis of the amyloid-ß (Aß) peptide. Genetic lesions underlying Alzheimer's disease (AD) can act by interfering with this physiological process. Specifically, proteins involved in trafficking between endosomal compartments and the trans-Golgi network (TGN) [including the retromer complex (Vps35, Vps26) and its putative receptors (sortilin, SorL1, SorCS1)] have been implicated in the molecular pathology of late-onset AD. Previously, we demonstrated a role for SorCS1 in APP metabolism and Aß production and, while we implicated a role for the retromer in this regulation, the underlying mechanism remained poorly understood. Here, we provide evidence for a motif within the SorCS1c cytoplasmic tail that, when manipulated, results in perturbed sorting of APP and/or its fragments to endosomal compartments, decreased retrograde TGN trafficking, and increased Aß production in H4 neuroglioma cells. These perturbations apparently do not involve turnover of the cell surface APP pool, but rather they involve intracellular APP and/or its fragments, downstream of APP endocytosis.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Citoplasma/metabolismo , Receptores de Superfície Celular/metabolismo , Motivos de Aminoácidos/genética , Motivos de Aminoácidos/fisiologia , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Biotinilação , Linhagem Celular Tumoral , Cicloeximida/farmacologia , Endocitose/efeitos dos fármacos , Endocitose/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Glioma/patologia , Humanos , Imunoprecipitação , Modelos Biológicos , Mutagênese Sítio-Dirigida/métodos , Mutação/genética , Mutação Puntual/genética , Inibidores da Síntese de Proteínas/farmacologia , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/genética , Receptores de Superfície Celular/genética , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismo , Tirosina/metabolismo
14.
Autophagy ; 9(4): 617-8, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23380933

RESUMO

Alzheimer disease (AD) is a form of neurodegeneration that develops over the course of multiple decades and as a result of the accumulation of the pathogenic amyloid-ß (Aß) peptide, also known as A4. In late-stage AD, failure of autophagic clearance results in neuronal cell bodies that are almost entirely consumed by autophagic vacuoles (AVs). Previously, we have shown that the potential AD drug latrepirdine (aka Dimebon(®)), a Russian antihistamine that has shown mixed results in phase II clinical trials in AD, regulates metabolism of the amyloid-ß/A4 precursor protein (APP). In two Molecular Psychiatry papers in 2012, we sought to determine the mechanism through which latrepirdine regulates APP metabolism and to determine, using an Alzheimer mouse model, whether latrepirdine provides protection from the toxicity associated with the accumulation of Aß. In cultured cells, we provided evidence that latrepirdine stimulates MTOR- and ATG5-dependent autophagy, leading to the reduction of intracellular levels of APP metabolites, including Aß. Consistent with this finding, we found that chronic latrepirdine administration resulted in increased levels of the biomarkers thought to correlate with autophagy activation in the brains of TgCRND8 (APP K670M, N671L, V717F) or wild-type mice, and that treatment was associated with abrogation of behavioral deficit, reduction in Aß neuropathology, and prevention of autophagic failure among TgCRND8 mice.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Autofagia/efeitos dos fármacos , Indóis/farmacologia , Indóis/uso terapêutico , Neurônios/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , alfa-Sinucleína/metabolismo
15.
Postdoc J ; 1(2): 21-34, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28286801

RESUMO

Macroautophagy (autophagy) is a conserved cellular pathway that regulates the degradation of long-lived proteins, protein aggregates, and cellular organelles. Autophagy is essential for maintaining neuronal homeostasis; however, neuronal autophagic efficiency decreases with age. Therefore, aging is one of the greatest risk factors for development of Alzheimer's disease (AD), a slowly progressing form of neurodegeneration that develops over the course of 10-20 years prior to the onset of overt clinical symptoms. AD is defined neuropathologically by the presence of extracellular aggregates of the amyloidogenic protein amyloid-ß (Aß) and intracellular accumulation of the microtubule-associated protein tau. At end-stage Alzheimer's disease, abnormal autophagic pathology has been reported in human brain and in multiple mouse models of AD, suggesting that an intimate association may exist between neuronal autophagy stasis and Alzheimer's-related pathology. Here, we highlight recent evidence that the autophagic pathway plays a role in both the generation and clearance of the pathogenic Aß protein and its precursors. The primary focus of this review is to examine the compelling research that highlights the autophagic pathway as a therapeutic target for AD and to discuss the therapeutic space around autophagy-regulating programs for AD. Finally, we propose that programs targeting autophagy regulation for AD ought to consider prophylactic or early stage intervention trials based on evidence against druggability of this pathway in late-stage disease.

16.
J Shoulder Elbow Surg ; 22(3): 381-6, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22947235

RESUMO

BACKGROUND: Interscalene brachial plexus block (ISBPB) provides excellent analgesia after rotator cuff surgery but is associated with diaphragm dysfunction. In this study, ISBPB with 20 mL of 0.125% or 0.25% bupivacaine were compared to assess the effect on diaphragm function, oxygen saturation, pain control, opioid requirements, and patient satisfaction. MATERIALS AND METHODS: In this prospective, randomized, double-blind study, 30 adults undergoing outpatient arthroscopic rotator cuff repair were enrolled to receive ultrasound-guided interscalene brachial plexus catheter placement with 20 mL of 0.125% (n = 15) or 0.25% bupivacaine (n = 15). Diaphragm function and oxygen saturation were assessed before ISBPB placement and on discharge from the postanesthesia care unit. Postoperative pain scores, opioid requirements, and patient satisfaction were compared. RESULTS: Diaphragm function and oxygen saturation were superior in the low concentration group. Absent or paradoxic motion of the diaphragm was present in 78% of the 0.25% group compared with 21% of patients in the 0.125% group (P = .008). Oxygen saturation decreased 4.3% in the 0.25% group compared with a decrease of 2.6% in the 0.125% group (P = .04). Pain scores averaged 1 of 10 in the 0.25% group and 0 of 10 in the 0.125% group (P = .02). Opioid requirements and patient satisfaction were not different between the two groups. CONCLUSIONS: In this randomized, double-blind comparison of ISBPB performed with 20 mL of 0.125% or 0.25% bupivacaine, diaphragm function and oxygen saturation were superior in patients treated with more dilute bupivacaine. Furthermore, there were no clinically significant differences in pain scores, and no statistically significant differences in opioid requirements and patient satisfaction.


Assuntos
Anestésicos Locais , Bupivacaína , Diafragma/efeitos dos fármacos , Bloqueio Nervoso , Dor Pós-Operatória/tratamento farmacológico , Manguito Rotador/cirurgia , Analgésicos Opioides/uso terapêutico , Artroscopia , Diafragma/diagnóstico por imagem , Diafragma/inervação , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oximetria , Medição da Dor , Satisfação do Paciente , Estudos Prospectivos , Lesões do Manguito Rotador , Ultrassonografia
17.
Front Neurol ; 3: 177, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23267342

RESUMO

Blast-induced traumatic brain injury (TBI) has been a major cause of morbidity and mortality in the conflicts in Iraq and Afghanistan. How the primary blast wave affects the brain is not well understood. In particular, it is unclear whether blast injures the brain through mechanisms similar to those found in non-blast closed impact injuries (nbTBI). The ß-amyloid (Aß) peptide associated with the development of Alzheimer's disease is elevated acutely following TBI in humans as well as in experimental animal models of nbTBI. We examined levels of brain Aß following experimental blast injury using enzyme-linked immunosorbent assays for Aß 40 and 42. In both rat and mouse models of blast injury, rather than being increased, endogenous rodent brain Aß levels were decreased acutely following injury. Levels of the amyloid precursor protein (APP) were increased following blast exposure although there was no evidence of axonal pathology based on APP immunohistochemical staining. Unlike the findings in nbTBI animal models, levels of the ß-secretase, ß-site APP cleaving enzyme 1, and the γ-secretase component presenilin-1 were unchanged following blast exposure. These studies have implications for understanding the nature of blast injury to the brain. They also suggest that strategies aimed at lowering Aß production may not be effective for treating acute blast injury to the brain.

18.
Mol Neurodegener ; 7: 58, 2012 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-23173713

RESUMO

BACKGROUND: The accumulation of amyloid beta (Aß) oligomers or fibrils is thought to be one of the main causes of synaptic and neuron loss, believed to underlie cognitive dysfunction in Alzheimer's disease (AD). Neuron loss has rarely been documented in amyloid precursor protein (APP) transgenic mouse models. We investigated whether two APP mouse models characterized by different folding states of amyloid showed different neuronal densities using an accurate method of cell counting. FINDINGS: We examined total cell and neuronal populations in Swedish/Indiana APP mutant mice (TgCRND8) with severe Aß pathology that includes fibrils, plaques, and oligomers, and Dutch APP mutant mice with only Aß oligomer pathology. Using the isotropic fractionator, we found no differences from control mice in regional total cell populations in either TgCRND8 or Dutch mice. However, there were 31.8% fewer hippocampal neurons in TgCRND8 compared to controls, while no such changes were observed in Dutch mice. CONCLUSIONS: We show that the isotropic fractionator is a convenient method for estimating neuronal content in milligram quantities of brain tissue and represents a useful tool to assess cell loss efficiently in transgenic models with different types of neuropathology. Our data support the hypothesis that TgCRND8 mice with a spectrum of Aß plaque, fibril, and oligomer pathology exhibit neuronal loss whereas Dutch mice with only oligomers, showed no evidence for neuronal loss. This suggests that the combination of plaques, fibrils, and oligomers causes more damage to mouse hippocampal neurons than Aß oligomers alone.


Assuntos
Doença de Alzheimer/patologia , Contagem de Células/métodos , Fracionamento Celular/métodos , Hipocampo/patologia , Neurônios/patologia , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos
19.
J Alzheimers Dis ; 32(4): 949-67, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22903131

RESUMO

Latrepirdine (Dimebon), an anti-histamine, has shown some benefits in trials of neurodegenerative diseases characterized by accumulation of aggregated or misfolded protein such as Alzheimer's disease (AD) and has been shown to promote the removal of α-synuclein protein aggregates in vivo. An important pathway for removal of aggregated or misfolded proteins is the autophagy-lysosomal pathway, which has been implicated in AD pathogenesis, and enhancing this pathway has been shown to have therapeutic potential in AD and other proteinopathies. Here we use a yeast model, Saccharomyces cerevisiae, to investigate whether latrepirdine can enhance autophagy and reduce levels of amyloid-ß (Aß)42 aggregates. Latrepirdine was shown to upregulate yeast vacuolar (lysosomal) activity and promote transport of the autophagic marker (Atg8) to the vacuole. Using an in vitro green fluorescent protein (GFP) tagged Aß yeast expression system, we investigated whether latrepirdine-enhanced autophagy was associated with a reduction in levels of intracellular GFP-Aß42. GFP-Aß42 was localized into punctate patterns compared to the diffuse cytosolic pattern of GFP and the GFP-Aß42 (19:34), which does not aggregate. In the autophagy deficient mutant (Atg8Δ), GFP-Aß42 showed a more diffuse cytosolic localization, reflecting the inability of this mutant to sequester GFP-Aß42. Similar to rapamycin, we observed that latrepirdine significantly reduced GFP-Aß42 in wild-type compared to the Atg8Δ mutant. Further, latrepirdine treatment attenuated Aß42-induced toxicity in wild-type cells but not in the Atg8Δ mutant. Together, our findings provide evidence for a novel mechanism of action for latrepirdine in inducing autophagy and reducing intracellular levels of GFP-Aß42.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Autofagia/fisiologia , Proteínas de Fluorescência Verde/metabolismo , Indóis/farmacologia , Líquido Intracelular/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Saccharomyces cerevisiae/metabolismo , Peptídeos beta-Amiloides/metabolismo , Autofagia/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Proteínas de Fluorescência Verde/antagonistas & inibidores , Humanos , Líquido Intracelular/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
20.
Adv Pharmacol ; 64: 213-71, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22840749

RESUMO

Currently, the field is awaiting the results of several pivotal Phase III clinical Alzheimer's disease (AD) trials that target amyloid-ß (Aß). In light of the recent biomarker studies that indicate Aß levels are at their most dynamic 5-10 years before the onset of clinical symptoms, it is becoming uncertain whether direct approaches to target Aß will achieve desired clinical efficacy. AD is a complex neurodegenerative disease caused by dysregulation of numerous neurobiological networks and cellular functions, resulting in synaptic loss, neuronal loss, and ultimately impaired memory. While it is clear that Aß plays a key role in the pathogenesis of AD, it may be a challenging and inefficient target for mid-to-late stage AD intervention. Throughout the course of AD, multiple pathways become perturbed, presenting a multitude of possible therapeutic avenues for design of AD intervention and prophylactic therapies. In this chapter, we sought to first provide an overview of Aß-directed strategies that are currently in development, and the pivotal Aß-targeted trials that are currently underway. Next, we delve into the biology and therapeutic designs associated with other key areas of research in the field including tau, protein trafficking and degradation pathways, ApoE, synaptic function, neurotrophic/neuroprotective strategies, and inflammation and energy utilization. For each area we have provided a comprehensive and balanced overview of the therapeutic strategies currently in preclinical and clinical development, which will shape the future therapeutic landscape of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Terapia de Alvo Molecular , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Ensaios Clínicos como Assunto , Descoberta de Drogas , Humanos
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