RESUMO
BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disease with pathological hallmarks including the formation of extracellular aggregates of amyloid-beta (Aß) known as plaques and intracellular tau tangles. Coincident with the formation of Aß plaques is recruitment and activation of glial cells to the plaque forming a plaque niche. In addition to histological data showing the formation of the niche, AD genetic studies have added to the growing appreciation of how dysfunctional glia pathways drive neuropathology, with emphasis on microglia pathways. Genomic approaches enable comparisons of human disease profiles between different mouse models informing on their utility to evaluate secondary changes to triggers such as Aß deposition. METHODS: In this study, we utilized two animal models of AD to examine and characterize the AD-associated pathology: the Tg2576 Swedish APP (KM670/671NL) and TgCRND8 Swedish plus Indiana APP (KM670/671NL + V717F) lines. We used laser capture microscopy (LCM) to isolate samples surrounding Thio-S positive plaques from distal non-plaque tissue. These samples were then analyzed using RNA sequencing. RESULTS: We determined age-associated transcriptomic differences between two similar yet distinct APP transgenic mouse models, known to differ in proportional amyloidogenic species and plaque deposition rates. In Tg2576, human AD gene signatures were not observed despite profiling mice out to 15 months of age. TgCRND8 mice however showed progressive and robust induction of lysomal, neuroimmune, and ITIM/ITAM-associated gene signatures overlapping with prior human AD brain transcriptomic studies. Notably, RNAseq analyses highlighted the vast majority of transcriptional changes observed in aging TgCRND8 cortical brain homogenates were in fact specifically enriched within the plaque niche samples. Data uncovered plaque-associated enrichment of microglia-related genes such as ITIM/ITAM-associated genes and pathway markers of phagocytosis. CONCLUSION: This work may help guide improved translational value of APP mouse models of AD, particularly for strategies aimed at targeting neuroimmune and neurodegenerative pathways, by demonstrating that TgCRND8 more closely recapitulates specific human AD-associated transcriptional responses.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Córtex Cerebral/metabolismo , Citocinas/metabolismo , Regulação da Expressão Gênica/genética , Fatores Etários , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Córtex Cerebral/patologia , Correlação de Dados , Modelos Animais de Doenças , Humanos , Microdissecção e Captura a Laser , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Mutação/genética , Placa Amiloide/patologia , RNA Mensageiro/metabolismo , TranscriptomaRESUMO
BACKGROUND: Magnetic resonance imaging has been recognized for years as the safest and most precise imaging method, particularly for children. The accuracy of MRI depends on avoidance of patient movement during the study. This may be difficult for children and may require anesthesia. OBJECTIVE: We evaluated an introductory instruction program as an assistive tool in performing MRI without anesthesia. MATERIALS AND METHODS: In one institution, 121 children were randomized to undergo full interactive pre-MRI instruction (n=64), which included an instructional booklet, movie and simulator practice, or partial instruction (n=57), comprised of the booklet only. All researchers and health care professionals involved, except for the one who instructed the families, were masked to the group allocation. Parents' anxiety, according to the Spielberger state anxiety inventory, was measured. RESULTS: Median age was 7.4 years (range: 5 years-16 years). Anesthesia was required for fewer children who received full compared to partial instruction: 17 (27%) vs. 27 (47%), P≤0.02. The median anxiety level prior to instruction was higher than the median level after instruction, for both the partial and full instruction groups. CONCLUSION: Instruction including simulator practice was associated with a decreased need for anesthesia among children undergoing MRI scans.
Assuntos
Anestesia/estatística & dados numéricos , Ansiedade/prevenção & controle , Imageamento por Ressonância Magnética , Educação de Pacientes como Assunto , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Estudos ProspectivosRESUMO
We investigated the role of Toll-like receptor 4 (TLR4), a major mediator of innate immune responses, on cognitive performance in a type 1 diabetes model (T1D). After administration of streptozotocin, both TLR4 knockout (TLR4 KO) and wild type (WT) diabetic mice displayed metabolic alterations similar to those observed in T1D patients, including increased levels of glucose, cholesterol, triglycerides and ketones. T1D mice exhibited cognitive impairment which was less severe in TLR4 KO mice compared to WT mice. WT mice with higher glucose and those with higher triglyceride levels exhibited significantly more anxiety and impaired memory compared to those with lower levels of glucose and triglycerides; these correlations were absent in TLR4 KO mice. Additional findings suggest roles for TLR4 signaling in modifying the expression of enzymes involved in energy metabolism in brain cells in the setting of T1D. Our data show that TLR4 contributes to the negative impact of T1D on anxiety and cognition.
Assuntos
Tonsila do Cerebelo/fisiopatologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/fisiopatologia , Modelos Animais de Doenças , Receptor 4 Toll-Like/metabolismo , Animais , Transtornos Cognitivos/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Masculino , Camundongos , Camundongos Knockout , EstreptozocinaRESUMO
Toll-like receptors (TLR) are innate immune receptors typically activated by microbial-associated molecular patterns (MAMPs) during infection or damage-associated molecular patterns (DAMPs) as a result of tissue injury. Recent findings suggest that TLR2 and TLR4 signaling play important roles in developmental and adult neuroplasticity, and in learning and memory. In addition, activation of TLR2 and TLR4 worsens ischemic injury to the heart and brain in animal models of myocardial infarction and stroke. TLR activation is also implicated in thermoregulation and fever in response to infection. However, it is not known whether TLRs participate in the regulation of the sympathetic and/or parasympathetic components of the autonomic nervous system (ANS). Here we provide evidence that TLR2 and TLR4 influence autonomic regulation of heart rate (HR) body temperature and energy metabolism in mice. We show that mice lacking TLR2 or TLR4 exhibit reduced basal HR, which results from an increase of parasympathetic tone. In addition, thermoregulatory responses to stress are altered in TLR2-/- and TLR4-/- mice, and brown fat-dependent thermoregulation is altered in TLR4-/- mice. Moreover, TLR2-/- and TLR4-/- mice consume less food and exhibit a greater mass compared to wild type mice. Collectively, our findings suggest important roles for TLR2 and TLR4 in the ANS regulation of cardiovascular function, thermoregulation, and energy metabolism.
Assuntos
Sistema Nervoso Autônomo/fisiologia , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Animais , Temperatura Corporal , Regulação da Temperatura Corporal/fisiologia , Metabolismo Energético/fisiologia , Frequência Cardíaca/fisiologia , Masculino , Camundongos , Camundongos Knockout , Restrição Física , Estresse Psicológico/metabolismoRESUMO
Laboratory and field-based studies of the invasive mosquito Aedes albopictus demonstrate its competency to transmit over twenty different pathogens linked to a broad range of vertebrate hosts. The vectorial capacity of Ae. albopictus to transmit these pathogens remains unclear, partly due to knowledge gaps regarding its feeding behavior. Blood meal analyses from field-captured specimens have shown vastly different feeding patterns, with a wide range of anthropophagy (human feeding) and host diversity. To address this knowledge gap, we asked whether differences in innate host preference may drive observed variation in Ae. albopictus feeding patterns in nature. Low generation colonies (F2-F4) were established with field-collected mosquitoes from three populations with high reported anthropophagy (Thailand, Cameroon, and Florida, USA) and three populations in the United States with low reported anthropophagy (New York, Maryland, and Virginia). The preference of these Ae. albopictus colonies for human versus non-human animal odor was assessed in a dual-port olfactometer along with control Ae. aegypti colonies already known to show divergent behavior in this assay. All Ae. albopictus colonies were less likely (p < 0.05) to choose the human-baited port than the anthropophilic Ae. aegypti control, instead behaving similarly to zoophilic Ae. aegypti. Our results suggest that variation in reported Ae. albopictus feeding patterns are not driven by differences in innate host preference, but may result from differences in host availability. This work is the first to compare Ae. albopictus and Ae. aegypti host preference directly and provides insight into differential vectorial capacity and human feeding risk.
Assuntos
Aedes , Animais , Odorantes , Comportamento Alimentar , Florida , TailândiaRESUMO
Ceruloplasmin (Cp) is a ferroxidase involved in iron metabolism by converting Fe(2+) to Fe(3+), and by regulating cellular iron efflux. In the ceruloplasmin knockout (CpKO) mouse, the deregulation of iron metabolism results in moderate liver and spleen hemosiderosis, but the impact of Cp deficiency on brain neurochemistry and behavior in this animal model is unknown. We found that in contrast to peripheral tissues, iron levels in the hippocampus are significantly reduced in CpKO mice. Although it does not cause any discernable deficits in motor function or learning and memory, Cp deficiency results in heightened anxiety-like behavior in the open field and elevated plus maze tests. This anxiety phenotype is associated with elevated levels of plasma corticosterone. Previous studies provided evidence that anxiety disorders and long-standing stress are associated with reductions in levels of serotonin (5HT) and brain-derived neurotrophic factor (BDNF) in the hippocampus. We found that levels of 5HT and norepinephrine (NE), and the expression of BDNF and its receptor trkB, are significantly reduced in the hippocampus of CpKO mice. Thus, Cp deficiency causes an anxiety phenotype by a mechanism that involves decreased levels of iron, 5HT, NE, and BDNF in the hippocampus.
Assuntos
Ansiedade/metabolismo , Ansiedade/psicologia , Fator Neurotrófico Derivado do Encéfalo/deficiência , Ceruloplasmina/deficiência , Hipocampo/metabolismo , Deficiências de Ferro , Serotonina/deficiência , Animais , Química Encefálica/genética , Ceruloplasmina/genética , Corticosterona/sangue , Medo/fisiologia , Elevação dos Membros Posteriores , Aprendizagem/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/fisiologia , Equilíbrio Postural/fisiologia , Desempenho Psicomotor/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Reconhecimento Psicológico/fisiologia , Transcrição GênicaRESUMO
The temperate United States has experienced increasing incidence of mosquito-borne diseases. Recent studies conducted in Baltimore, MD have demonstrated a negative relationship between abundances of Aedes albopictus (Skuse) and Culex mosquitoes and mean neighborhood income level, but have not looked at the presence of pathogens. Mosquitoes collected from five socioeconomically variable neighborhoods were tested for infection by West Nile, chikungunya, and Zika viruses in 2015 and 2016, and again from four of the neighborhoods in 2017. Minimum infection rates of pooled samples were compared among neighborhoods for each year, as well as among individual blocks in 2017. West Nile virus was detected in both Ae. albopictus and Culex pools from all neighborhoods sampled in 2015 and 2017. No infected pools were detected in any year for chikungunya or Zika viruses, and none of the target viruses were detected in 2016. Infection rates were consistently higher for Culex than for Ae. albopictus. Minimum infection rate was negatively associated with mean neighborhood income for both species in 2015. Although earlier work has shown a positive association between block-level abandonment and mosquito abundance, no association was detected in this study. Still, we demonstrate that viral infection in mosquito pools can differ substantially across adjacent urban neighborhoods that vary by income. Though trap security and accessibility often inform city sampling locations, detecting and managing arboviral risk requires surveillance across neighborhoods that vary in socioeconomics, including lower income areas that may be less accessible and secure but have higher infection rates.
Assuntos
Aedes/virologia , Culex/virologia , População Urbana/estatística & dados numéricos , Vírus do Nilo Ocidental/fisiologia , Animais , Baltimore , Pobreza , Febre do Nilo Ocidental/transmissãoRESUMO
This protocol describes the generation of protoplasts from protonemal tissue of the moss Physcomitrium patens (syn. Physcomitrella patens), using Cellulase ONOZUKA R10 and Macerozyme R10, followed by polyethylene glycol (PEG) mediated transformation. The protonemal tissue grown in liquid suspension was harvested and treated with enzyme cocktails mix of 1.5% Cellulase ONOZUKA R10 and 0.5% Macerozyme R10 to generate 1,8 million protoplasts within 3 h.
RESUMO
Although spinal glia acquire a reactive profile in radiculopathy, glial cell proliferation remains largely unstudied. This study investigated spinal glial proliferation in a model simulating painful disc herniation; the C7 nerve root underwent compression and chromic gut suture exposure or sham procedures. A subset of injured rats received minocycline injections prior to injury. Allodynia was assessed and bromodeoxyuridine (BrdU) was injected 2 hr before tissue harvest on day 1 or 3. Spinal cell proliferation and phenotype identification were assayed by fluorescent colabeling with antibodies to BrdU and either glial fibrillary acidic protein (astrocytes) or Iba1 (microglia). At day 1, ipsilateral allodynia was significantly increased (P < 0.001) for injury over sham. Minocycline treatment significantly decreased ipsilateral allodynia to sham levels at day 1 (P < 0.001). At day 3, ipsilateral allodynia remained and contralateral allodynia was also present for injury (P< 0.003) over sham. The number of BrdU-positive cells in the ipsilateral spinal dorsal horn at day 1 after injury was significantly elevated (P < 0.001) over sham. Approximately 70% of BrdU-positive cells labeled positively for Iba1; dividing microglia were significantly increased (P < 0.004) in the ipsilateral dorsal horn at day 1 following injury compared with sham. Spinal cellular proliferation after injury was not changed by minocycline injection. By day 3, the number of BrdU-positive cells had returned to sham levels bilaterally. Data indicate that spinal microglia proliferate after injury but that proliferation is not abolished by minocycline treatment that attenuates allodynia, indicating that spinal microglial proliferation may be related to injury and may not be linked to changes in sensory perception.
Assuntos
Gliose/fisiopatologia , Hiperalgesia/fisiopatologia , Deslocamento do Disco Intervertebral/complicações , Microglia/fisiologia , Radiculopatia/fisiopatologia , Medula Espinal/fisiopatologia , Animais , Antibacterianos/farmacologia , Comportamento Animal/fisiologia , Biomarcadores , Bromodesoxiuridina , Proteínas de Ligação ao Cálcio/metabolismo , Divisão Celular/efeitos dos fármacos , Divisão Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Lateralidade Funcional/fisiologia , Proteína Glial Fibrilar Ácida/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Masculino , Proteínas dos Microfilamentos , Microglia/patologia , Minociclina/farmacologia , Radiculopatia/tratamento farmacológico , Radiculopatia/etiologia , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Over-treatment of acute otitis media (AOM) with antibiotics is common, and poses a high burden on health-care systems. METHODS: Records of children 6-36 months of age with AOM visiting a university-affiliated pediatric emergency department between 2014 and 2016 were reviewed for the treatment given: watchful waiting versus antibiotics. If antibiotics were prescribed, the type and duration were recorded. We evaluated appropriate and inappropriate treatment rates of eligible AOM cases, in respect to the local guidelines, which encourage watchful waiting in most mild-moderate cases. RESULTS: Out of 1493 AOM visits, 863 (57.8%) were boys, with a median age of 14.9 months (interquartile range, 9-19). The overall pre-visit antibiotic rate was 24.1%, but among those children examined by a physician, this rate was 95.2%. Amoxicillin was the most common antibiotic, administered in 66.3% of the cases. Only 21 children (5.8%) had been treated with antibiotics for ≥7 days before their visit, and were considered as treatment failure. Antibiotic therapy upon discharge was recorded in 1394/1449 visits (96.2%), again with amoxicillin as the most common antibiotic therapy, in 80.8% of the cases. In these visits, the average duration of antibiotic treatment was 8.29 days. Appropriateness of treatment (watchful waiting or antibiotics) could be analyzed in 1134 visits; 20.9% were considered as inappropriate. Of them, 98.3% were prescribed with the wrong antibiotic type and duration. CONCLUSIONS: Adherence rate to the local guidelines treatment recommendations for uncomplicated AOM was high, as measured by whether appropriate treatment was given and type and duration of antibiotics.
Assuntos
Serviço Hospitalar de Emergência , Hospitais Pediátricos , Prescrição Inadequada/estatística & dados numéricos , Otite Média/tratamento farmacológico , Padrões de Prática Médica/estatística & dados numéricos , Doença Aguda , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Pré-Escolar , Estudos Transversais , Feminino , Fidelidade a Diretrizes , Humanos , Lactente , Masculino , Alta do Paciente , Estudos RetrospectivosRESUMO
Both chemical irritation and mechanical compression affect radicular pain from disc herniation. However, relative effects of these insults on pain symptoms are unclear. This study investigated chemical and mechanical contributions for painful cervical nerve root injury. Accordingly, the C7 nerve root separately underwent chromic gut exposure, 10gf compression, or their combination. Mechanical allodynia was assessed, and glial reactivity in the C7 spinal cord tissue was assayed at days 1 and 7 by immunohistochemistry using GFAP and OX-42 as markers of astrocytes and microglia, respectively. Both chromic gut irritation and 10gf compression produced ipsilateral increases in allodynia over sham (p<0.048); combining the two insults significantly (p<0.027) increased ipsilateral allodynia compared to either insult alone. Behavioral hypersensitivity was also produced in the contralateral forepaw for all injuries, but only the combined insult was significantly increased over sham (p<0.031). Astrocytic activation was significantly increased over normal (p<0.001) in the ipsilateral dorsal horn at 1 day after either compression or the combined injury. By day 7, GFAP-reactivity was further increased for the combined injury compared to day 1 (p<0.001). In contrast, spinal OX-42 staining was generally variable, with only mild activation at day 1. By day 7 after the combined injury, there were significant (p<0.003) bilateral increases in OX-42 staining over normal. Spinal astrocytic and microglial reactivity follow different patterns after chemical root irritation, compression, and a combined insult. The combination of transient compression and chemical irritation produces sustained bilateral hypersensitivity, sustained ipsilateral spinal astrocytic activation and late onset bilateral spinal microglial activation.
Assuntos
Síndromes de Compressão Nervosa/fisiopatologia , Neuroglia/imunologia , Limiar da Dor , Radiculopatia/fisiopatologia , Raízes Nervosas Espinhais/fisiopatologia , Animais , Comportamento Animal , Vértebras Cervicais , Lateralidade Funcional , Deslocamento do Disco Intervertebral/complicações , Deslocamento do Disco Intervertebral/imunologia , Masculino , Síndromes de Compressão Nervosa/complicações , Síndromes de Compressão Nervosa/imunologia , Radiculopatia/induzido quimicamente , Radiculopatia/complicações , Radiculopatia/imunologia , Ratos , Ratos Sprague-Dawley , Medula Espinal/citologia , Medula Espinal/imunologia , Raízes Nervosas Espinhais/imunologia , Raízes Nervosas Espinhais/patologiaRESUMO
Parkinson's disease (PD) patients frequently display loss of body fat mass and increased energy expenditure, and several studies have outlined a relationship between these metabolic abnormalities and disease severity, yet energy metabolism is largely unstudied in mouse models of PD. Here we characterize metabolic and physiologic responses to a high calorie diet (HCD) in mice expressing in neurons a mutant form of human α-synuclein (A53T) that causes dominantly inherited familial forms of the disease. A53T (SNCA) and wild type (WT) littermate mice were placed on a HCD for 12 weeks and evaluated for weight gain, food intake, body fat, blood plasma leptin, hunger, glucose tolerance, and energy expenditure. Results were compared with both SNCA and WT mice on a control diet. Despite consuming similar amounts of food, WT mice gained up to 66% of their original body weight on a HCD, whereas SNCA mice gained only 17%. Further, after 12 weeks on a HCD, magnetic resonance imaging analysis revealed that WT mice had significantly greater total and visceral body fat compared with SNCA mice (p < 0.007). At the age of 24 weeks SNCA mice displayed significantly increased hunger compared with WT (p < 0.03). At the age of 36 weeks, SNCA mice displayed significant hypoleptinemia compared with WT, both on a normal diet and a HCD (p < 0.03). The HCD induced insulin insensitivity in WT, but not SNCA mice, as indicated by an oral glucose tolerance test. Finally, SNCA mice displayed greater energy expenditure compared with WT, as measured in a Comprehensive Laboratory Animal Monitoring System, after 12 weeks on a HCD. Thus, SNCA mice are resistant to HCD-induced obesity and insulin resistance and display reduced body fat, increased hunger, hypoleptinemia and increased energy expenditure. Our findings reveal a profile of metabolic dysfunction in a mouse model of PD that is similar to that of human PD patients, thus providing evidence that α-synuclein pathology is sufficient to drive such metabolic abnormalities and providing an animal model for discovery of the underlying mechanisms and potential therapeutic interventions.
Assuntos
Metabolismo Energético , Leptina/sangue , Leptina/deficiência , Mutação , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , alfa-Sinucleína/genética , Tecido Adiposo/metabolismo , Animais , Modelos Animais de Doenças , Ingestão de Energia , Resistência à Insulina , Masculino , CamundongosRESUMO
Age-associated dysregulation of sleep can be worsened by Alzheimer's disease (AD). AD and sleep restriction both impair cognition, yet it is unknown if mild chronic sleep restriction modifies the proteopathic processes involved in AD. The goal of this work was to test the hypothesis that sleep restriction worsens memory impairments, and amyloid ß-peptide (Aß) and pTau accumulations in the brain in a mouse model of AD, with a focus on a role for circulating glucocorticoids (GC). Male 3xTgAD mice were subjected to sleep restriction (SR) for 6h/day for 6 weeks using the modified multiple platform technique, and behavioral (Morris water maze, fear conditioning, open field) and biochemical (immunoblot) outcomes were compared to mice undergoing daily cage transfers (large cage control; LCC) as well as control mice that remained in their home cage (control; CTL). At one week, both LCC and SR mice displayed significant elevations in plasma corticosterone compared to CTL (p<0.002). By four weeks, SR mice displayed a two-fold increase in circulating corticosterone levels compared to CTL. Behavioral data indicated deficits in contextual and cued memory in SR mice that were not present for LCC or CTL (p<0.04). Both Aß and pTau levels increased in the cortex of SR mice compared to CTL and LCC; however these changes were not noted in the hippocampus. Significant positive correlations between cortical Aß and pTau levels and circulating corticosterone indicate a potential role for GCs in mediating behavioral and biochemical changes observed after sleep restriction in a mouse model of AD.
Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Córtex Cerebral/metabolismo , Transtornos da Memória/etiologia , Privação do Sono/fisiopatologia , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Condicionamento Psicológico/fisiologia , Corticosterona/sangue , Modelos Animais de Doenças , Comportamento Exploratório , Medo/psicologia , Humanos , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/sangue , Camundongos , Camundongos Transgênicos , Mutação/genética , Presenilina-1/genética , Proteínas tau/genéticaRESUMO
BACKGROUND: Mutations in the human α-synuclein gene lead to early-onset Parkinson's disease (PD); however, phenotypes of α-synuclein mutant mice vary depending upon the promoter driving transgene expression. OBJECTIVE: The goal of this study was to characterize behavior and neurochemical alterations in mice expressing mutant (A53T) human α-synuclein, controlled by a neuron-specific Thy-1 promoter. Our data provide important additional phenotypic and biochemical characterization of a previously generated model of PD. METHODS: A53T (SNCA) and wild type (WT) littermate mice were evaluated for motor function (rotarod and stride length) and anxiety (elevated plus maze and open field) every 2 weeks. At 24 weeks mice were evaluated in a Comprehensive Lab Animal Monitoring System (CLAMS). A separate cohort of mice were euthanized at 12, 24 and 36 weeks for immunoblot analysis of α-synuclein, dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the striatum, and hypothalamic serotonin and metabolites were measured. RESULTS: SNCA mice display significant motor deficits at 14-18 weeks of age compared to WT mice, which progress over time. CLAMS analysis revealed an increase in activity during the dark phase and a reduction in overall estimated sleep time for SNCA mice compared to WT consistent with clinical reports of sleep abnormalities in PD. A transient change in the levels of DAT appeared at 12 weeks in the striatum and serotonin levels were also altered in the hypothalamus at this time point. CONCLUSIONS: This PD model displays consistent and clinically relevant motor and sleep phenotypes. Anxiety phenotypes are consistent with other α-synuclein based PD models yet incongruous with typical clinical symptoms. Early increases in serotonin levels potentially explain reductions in anxiety behaviors and sleep.
Assuntos
Ansiedade/etiologia , Encéfalo/patologia , Regulação da Expressão Gênica , Proteínas de Filamentos Intermediários/genética , Mutação/genética , Doença de Parkinson , Transtornos do Sono-Vigília/etiologia , Fatores Etários , Animais , Ansiedade/diagnóstico , Encéfalo/metabolismo , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Comportamento Exploratório/fisiologia , Humanos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Transgênicos , Doença de Parkinson/complicações , Doença de Parkinson/genética , Doença de Parkinson/patologia , Desempenho Psicomotor/fisiologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Parkinson's disease (PD) patients often exhibit impaired regulation of heart rate by the autonomic nervous system (ANS) that may precede motor symptoms in many cases. Results of autopsy studies suggest that brainstem pathology, including the accumulation of α-synuclein, precedes damage to dopaminergic neurons in the substantia nigra in PD. However, the molecular and cellular mechanisms responsible for the early dysfunction of brainstem autonomic neurons are unknown. Here we report that mice expressing a mutant form of α-synuclein that causes familial PD exhibit aberrant autonomic control of the heart characterized by elevated resting heart rate and an impaired cardiovascular stress response, associated with reduced parasympathetic activity and accumulation of α-synuclein in the brainstem. These ANS abnormalities occur early in the disease process. Adverse effects of α-synuclein on the control of heart rate are exacerbated by a high energy diet and ameliorated by intermittent energy restriction. Our findings establish a mouse model of early dysregulation of brainstem control of the cardiovascular system in PD, and further suggest the potential for energy restriction to attenuate ANS dysfunction, particularly in overweight individuals.
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Doenças do Sistema Nervoso Autônomo/genética , Tronco Encefálico , Ingestão de Energia , Frequência Cardíaca , Doença de Parkinson/genética , alfa-Sinucleína , Animais , Doenças do Sistema Nervoso Autônomo/complicações , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Tronco Encefálico/metabolismo , Tronco Encefálico/fisiopatologia , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Doença de Parkinson/complicações , Doença de Parkinson/fisiopatologia , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders and exact a burden on our society greater than cardiovascular disease and cancer combined. While cognitive and motor symptoms are used to define AD and PD, respectively, patients with both disorders exhibit sleep disturbances including insomnia, hypersomnia and excessive daytime napping. The molecular basis of perturbed sleep in AD and PD may involve damage to hypothalamic and brainstem nuclei that control sleep-wake cycles. Perturbations in neurotransmitter and hormone signaling (e.g., serotonin, norepinephrine and melatonin) and the neurotrophic factor BDNF likely contribute to the disease process. Abnormal accumulations of neurotoxic forms of amyloid ß-peptide, tau and α-synuclein occur in brain regions involved in the regulation of sleep in AD and PD patients, and are sufficient to cause sleep disturbances in animal models of these neurodegenerative disorders. Disturbed regulation of sleep often occurs early in the course of AD and PD, and may contribute to the cognitive and motor symptoms. Treatments that target signaling pathways that control sleep have been shown to retard the disease process in animal models of AD and PD, suggesting a potential for such interventions in humans at risk for or in the early stages of these disorders.
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Doença de Alzheimer/fisiopatologia , Encéfalo/fisiopatologia , Doença de Parkinson/fisiopatologia , Transtornos do Sono-Vigília/fisiopatologia , Doença de Alzheimer/complicações , Animais , Encéfalo/anatomia & histologia , Modelos Animais de Doenças , Humanos , Doença de Parkinson/complicações , Transtornos do Sono-Vigília/etiologiaRESUMO
Overweight sedentary individuals are at increased risk for cardiovascular disease, diabetes, and some neurological disorders. Beneficial effects of dietary energy restriction (DER) and exercise on brain structural plasticity and behaviors have been demonstrated in animal models of aging and acute (stroke and trauma) and chronic (Alzheimer's and Parkinson's diseases) neurological disorders. The findings described later, and evolutionary considerations, suggest brain-derived neurotrophic factor (BDNF) plays a critical role in the integration and optimization of behavioral and metabolic responses to environments with limited energy resources and intense competition. In particular, BDNF signaling mediates adaptive responses of the central, autonomic, and peripheral nervous systems from exercise and DER. In the hypothalamus, BDNF inhibits food intake and increases energy expenditure. By promoting synaptic plasticity and neurogenesis in the hippocampus, BDNF mediates exercise- and DER-induced improvements in cognitive function and neuroprotection. DER improves cardiovascular stress adaptation by a mechanism involving enhancement of brainstem cholinergic activity. Collectively, findings reviewed in this paper provide a rationale for targeting BDNF signaling for novel therapeutic interventions in a range of metabolic and neurological disorders.
Assuntos
Sistema Nervoso Autônomo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Doenças Cardiovasculares/metabolismo , Sistema Nervoso Central/metabolismo , Metabolismo Energético , Animais , Restrição Calórica , Cognição , Ingestão de Alimentos , Exercício Físico , Hipocampo/metabolismo , Humanos , Hipotálamo/metabolismo , Camundongos , Plasticidade Neuronal , ObesidadeRESUMO
Alzheimer's disease and other related neurodegenerative diseases are highly debilitating disorders that affect millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited efficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symptoms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for major neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic dysregulation in Alzheimer's disease, Huntington's disease, and Parkinson's disease, and discuss several potential mechanisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degeneration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and 'eumetabolic' activities may possess superior efficacies compared to less pluripotent remedies.
Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Doenças Metabólicas/etiologia , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/metabolismo , Adiponectina/metabolismo , Peso Corporal , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Grelina/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Humanos , Leptina/metabolismoRESUMO
Chronic stress may be a risk factor for developing Alzheimer's disease (AD), but most studies of the effects of stress in models of AD utilize acute adverse stressors of questionable clinical relevance. The goal of this work was to determine how chronic psychosocial stress affects behavioral and pathological outcomes in an animal model of AD, and to elucidate underlying mechanisms. A triple-transgenic mouse model of AD (3xTgAD mice) and nontransgenic control mice were used to test for an affect of chronic mild social stress on blood glucose, plasma glucocorticoids, plasma insulin, anxiety, and hippocampal amyloid ß-particle (Aß), phosphorylated tau (ptau), and brain-derived neurotrophic factor (BDNF) levels. Despite the fact that both control and 3xTgAD mice experienced rises in corticosterone during episodes of mild social stress, at the end of the 6-week stress period 3xTgAD mice displayed increased anxiety, elevated levels of Aß oligomers and intraneuronal Aß, and decreased brain-derived neurotrophic factor levels, whereas control mice did not. Findings suggest 3xTgAD mice are more vulnerable than control mice to chronic psychosocial stress, and that such chronic stress exacerbates Aß accumulation and impairs neurotrophic signaling.
Assuntos
Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/metabolismo , Ansiedade/etiologia , Comportamento Animal/fisiologia , Comportamento Social , Estresse Psicológico/fisiopatologia , Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Glicemia/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Jejum , Glucocorticoides/sangue , Hipocampo/patologia , Humanos , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Presenilina-1/genética , Fatores de Tempo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Alzheimer's disease (AD) is an incurable and progressive neurodegenerative senile disorder associated with the brain accumulation of Aß plaques. Although vaccines that reduce Aß plaques can control AD, the rationale for their use at the onset of the disease remains debatable. Old humans and mice usually respond poorly to vaccines due to presumably age-related immunological impairments. Here, we report that by modifying vaccines, the poor responsiveness of old mice can be reversed. Unlike the Aß peptide vaccine, DNA immunizations with the amino-terminal Aß(1-11) fragment exposed on the surface of HBsAg particles elicit high levels of anti-Aß antibody both in young and old mice. Importantly, in AD model 3xTgAD mice, the vaccine reduced Aß plaques, ameliorated cognitive impairments and, surprisingly, significantly increased life span. Hence, we propose that vaccines targeting Aß(1-11) can efficiently combat AD-induced pathological alterations and provide survival benefit in patients with AD.