RESUMO
Autophagy is a highly conserved catabolic mechanism by which unnecessary or dysfunctional cellular components are removed. The dysregulation of autophagy has been implicated in various neurodegenerative diseases, including Alzheimer's disease (AD). Understanding the molecular mechanism(s)/molecules that influence autophagy may provide important insights into developing therapeutic strategies against AD and other neurodegenerative disorders. Engulfment adaptor phosphotyrosine-binding domain-containing protein 1 (GULP1) is an adaptor that interacts with amyloid precursor protein (APP) to promote amyloid-ß peptide production via an unidentified mechanism. Emerging evidence suggests that GULP1 has a role in autophagy. Here, we show that GULP1 is involved in autophagy through an interaction with autophagy-related 14 (ATG14), which is a regulator of autophagosome formation. GULP1 potentiated the stimulatory effect of ATG14 on autophagy by modulating class III phosphatidylinositol 3-kinase complex 1 (PI3KC3-C1) activity. The effect of GULP1 is attenuated by a GULP1 mutation (GULP1m) that disrupts the GULP1-ATG14 interaction. Conversely, PI3KC3-C1 activity is enhanced in cells expressing APP but not in those expressing an APP mutant that does not bind GULP1, which suggests a role of GULP1-APP in regulating PI3KC3-C1 activity. Notably, GULP1 facilitates the targeting of ATG14 to the endoplasmic reticulum (ER). Moreover, the levels of both ATG14 and APP are elevated in the autophagic vacuoles (AVs) of cells expressing GULP1, but not in those expressing GULP1m. APP processing is markedly enhanced in cells co-expressing GULP1 and ATG14. Hence, GULP1 alters APP processing by promoting the entry of APP into AVs. In summary, we unveil a novel role of GULP1 in enhancing the targeting of ATG14 to the ER to stimulate autophagy and, consequently, APP processing.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Precursor de Proteína beta-Amiloide , Proteínas Relacionadas à Autofagia , Autofagia , Humanos , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Células HEK293 , Ligação Proteica , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Classe III de Fosfatidilinositol 3-Quinases/genética , Proteínas de Transporte Vesicular/metabolismo , Proteínas de Transporte Vesicular/genéticaRESUMO
Circadian rhythms regulate physiological processes in approximately 24 h cycles, and their disruption is associated with various diseases. Inflammation may perturb circadian rhythms, though these interactions remain unclear. This study examined whether systemic inflammation induced by an intraperitoneal injection of lipopolysaccharide (LPS) could alter central and peripheral circadian rhythms and diurnal neuroimmune dynamics. Mice were randomly assigned to two groups: the saline control group and the LPS group. The diurnal expression of circadian clock genes and inflammatory cytokines were measured in the hypothalamus, hippocampus, and liver. Diurnal dynamic behaviors of microglia were also assessed. Our results revealed that the LPS perturbed circadian gene oscillations in the hypothalamus, hippocampus, and liver. Furthermore, systemic inflammation induced by the LPS could trigger neuroinflammation and perturb the diurnal dynamic behavior of microglia in the hippocampus. These findings shed light on the intricate link between inflammation and circadian disruption, underscoring their significance in relation to neurodegenerative diseases.
Assuntos
Ritmo Circadiano , Inflamação , Lipopolissacarídeos , Animais , Camundongos , Masculino , Microglia/metabolismo , Microglia/imunologia , Hipotálamo/metabolismo , Hipotálamo/imunologia , Hipocampo/metabolismo , Citocinas/metabolismo , Fígado/metabolismo , Fígado/patologia , Fígado/imunologia , Camundongos Endogâmicos C57BL , Relógios Circadianos/genética , NeuroimunomodulaçãoRESUMO
INTRODUCTION: Glucose transporter 1 (GLUT1) is essential for glucose transport into the brain and is predominantly expressed in the cerebral microvasculature. Downregulation of GLUT1 precedes the development of cognitive impairment in neurodegenerative conditions. Surgical trauma induces blood-brain barrier (BBB) disruption, neuroinflammation, neuronal mitochondria dysfunction, and acute cognitive impairment. We hypothesized that surgery reduces the expression of GLUT1 in the BBB that in turn disrupts its integrity and contributes to metabolic dysregulation in the brain that culminates in postoperative cognitive impairment. METHODOLOGY: Using an abdominal surgery model in aged WT mice, we assessed the perioperative changes in cognitive performance, tight junction proteins expression, GLUT1 expression, and the associated metabolic effects in the hippocampus. Thereafter, we evaluated the effects of these parameters in aged mice with conditional overexpression of GLUT1, and then again in aged mice with conditional overexpression of GLUT1 with or without prior exposure to the GLUT1 inhibitor ST-31. RESULTS: We showed a significant decline in cognitive performance, along with GLUT1 reduction and diminished glucose metabolism, especially in the ATP level in the postoperative mice compared with controls. Overexpression of GLUT1 expression alleviated postoperative cognitive decline and improved metabolic profiles, especially in adenosine, but did not directly restore ATP generation to control levels. GLUT1 inhibition ameliorated the postoperative beneficial effects of GLUT1 overexpression. CONCLUSIONS: Surgery-induced GLUT1 reduction significantly contributes to postoperative cognitive deficits in aged mice by affecting glucose metabolism in the brain. It indicates the potential of targeting GLUT1 to ameliorate perioperative neurocognitive disorders.
Assuntos
Barreira Hematoencefálica , Transtornos Cognitivos , Animais , Camundongos , Trifosfato de Adenosina/metabolismo , Barreira Hematoencefálica/metabolismo , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Regulação para Baixo , Glucose/metabolismo , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Microvasos/metabolismoRESUMO
BACKGROUND: Systemic activation of the immune system can exert detrimental effects on the central nervous system. Periodontitis, a chronic disease of the oral cavity, is a common source of systemic inflammation. Neuroinflammation might be a result of this to accelerate progressive deterioration of neuronal functions during aging or exacerbate pre-existing neurodegenerative diseases, such as Alzheimer's disease. With advancing age, the progressive increase in the body's pro-inflammatory status favors the state of vulnerability to both periodontitis and Alzheimer's disease. In the present study, we sought to delineate the roles of cytokines in the pathogenesis of both diseases. METHODS: To examine the impacts of periodontitis on the onset and progression of Alzheimer's disease, 6-month-old female 3 × Tg-AD mice and their age-matched non-transgenic mice were employed. Periodontitis was induced using two different experimental models: heat-killed bacterial-induced periodontitis and ligature-induced periodontitis. To delineate the roles of pro-inflammatory cytokines in the pathogenesis of periodontitis and Alzheimer's disease, interleukin 1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) were also injected into the buccal mandibular vestibule of mice. RESULTS: Here, we show that IL-1ß and TNF-α were two of the most important and earliest cytokines upregulated upon periodontal infection. The systemic upregulation of these two cytokines promoted a pro-inflammatory environment in the brain contributing to the development of Alzheimer's disease-like pathology and cognitive dysfunctions. Periodontitis-induced systemic inflammation also enhanced brain inflammatory responses and subsequently exacerbated Alzheimer's disease pathology and cognitive impairment in 3 × Tg-AD mice. The role of inflammation in connecting periodontitis to Alzheimer's disease was further affirmed in the conventional magnetization transfer experiment in which increased glial responses resulting from periodontitis led to decreased magnetization transfer ratios in the brain of 3 × Tg-AD mice. CONCLUSIONS: Systemic inflammation resulting from periodontitis contributed to the development of Alzheimer's disease tau pathology and subsequently led to cognitive decline in non-transgenic mice. It also potentiated Alzheimer's disease pathological features and exacerbated impairment of cognitive function in 3 × Tg-AD mice. Taken together, this study provides convincing evidence that systemic inflammation serves as a connecting link between periodontitis and Alzheimer's disease.
Assuntos
Doença de Alzheimer , Periodontite , Feminino , Camundongos , Animais , Fator de Necrose Tumoral alfa , Doença de Alzheimer/patologia , Interleucina-1beta , Inflamação , Citocinas , Camundongos TransgênicosRESUMO
BACKGROUND: Postoperative neurocognitive dysfunction remains a significant problem in vulnerable groups such as the elderly. While experimental data regarding its possible pathogenic mechanisms accumulate, therapeutic options for this disorder are limited. In this study, we evaluated the neuroprotective effect of a period of preconditioning resistant training on aged mice undergoing abdominal surgery. Further, we examined the underlying mechanisms from the perspective of neuroinflammatory state and synaptic plasticity in the hippocampus. METHODS: 18-month-old C57BL/6N mice were trained for 5 weeks using a ladder-climbing protocol with progressively increasing weight loading. Preoperative baseline body parameters, cognitive performance and neuroinflammatory states were assessed and compared between sedentary and trained groups of 9-month-old and 18-month-old mice. To access the neuroprotective effect of resistance training on postoperative aged mice, both sedentary and trained mice were subjected to a laparotomy under 3% sevoflurane anesthesia. Cognitive performance on postoperative day 14, hippocampal neuroinflammation, mitochondrial dysfunction and synaptic plasticity were examined and compared during groups. RESULTS: 18-month-old mice have increased body weight, higher peripheral and central inflammatory status, reduction in muscle strength and cognitive performance compared with middle-aged 9-month-old mice, which were improved by resistance exercise. In the laparotomy group, prehabilitative resistant exercise improved cognitive performance and synaptic plasticity, reduced inflammatory factors and glial cells activation after surgery. Furthermore, resistance exercise activated hippocampal PGC-1α/BDNF/Akt/GSK-3ß signaling and improved mitochondrial biogenesis, as well as ameliorated mitochondrial dynamics in postoperative-aged mice. CONCLUSIONS: Resistance exercise reduced risk factors for perioperative neurocognitive disorders such as increased body weight, elevated inflammatory markers, and pre-existing cognitive impairment. Accordantly, preoperative resistance exercise improved surgery-induced adverse effects including cognitive impairment, synaptic deficit and neuroinflammation, possibly by facilitate mitochondrial health through the PGC1-a/BDNF pathway.
Assuntos
Disfunção Cognitiva , Fármacos Neuroprotetores , Treinamento Resistido , Idoso , Animais , Peso Corporal , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/prevenção & controle , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Transtornos Neurocognitivos/etiologia , Transtornos Neurocognitivos/prevenção & controle , Doenças Neuroinflamatórias , Fármacos Neuroprotetores/farmacologia , Treinamento Resistido/métodosRESUMO
The increasing amount of particulate matter (PM) in the ambient air is a pressing public health issue globally. Epidemiological studies involving data from millions of patients or volunteers have associated PM with increased risk of dementia and Alzheimer's disease in the elderly and cognitive dysfunction and neurodegenerative pathology across all age groups, suggesting that PM may be a risk factor for neurodegenerative diseases. Neurodegenerative diseases affect an increasing population in this aging society, putting a heavy burden on economics and family. Therefore, understanding the mechanism by which PM contributes to neurodegeneration is essential to develop effective interventions. Evidence in human and animal studies suggested that PM induced neurodenegerative-like pathology including neurotoxicity, neuroinflammation, oxidative stress, and damage in blood-brain barrier and neurovascular units, which may contribute to the increased risk of neurodegeneration. Interestingly, antagonizing oxidative stress alleviated the neurotoxicity of PM, which may underlie the essential role of oxidative stress in PM's potential effect in neurodegeneration. This review summarized up-to-date epidemiological and experimental studies on the pathogenic role of PM in neurodegenerative diseases and discussed the possible underlying mechanisms.
Assuntos
Doença de Alzheimer , Material Particulado , Idoso , Envelhecimento , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/etiologia , Animais , Humanos , Estresse Oxidativo , Material Particulado/toxicidadeRESUMO
Perioperative neurocognitive disorders are frequently observed in postoperative patients and previous reports have shown that pre-existing mild cognitive impairment with accumulated neuropathology may be a risk factor. Sevoflurane is a general anesthetic agent which is commonly used in clinical practice. However, the effects of sevoflurane in postoperative subjects are still controversial, as both neurotoxic or neuroprotective effects were reported. The purpose of this study is to investigate the effects of sevoflurane in 3 × Tg mice, a specific animal model with pre-existing Alzheimer's disease neuropathology. 3 × Tg mice and wild-type mice were exposed to 2 h of sevoflurane respectively. Cognitive function, glutamate transporter expression, MAPK kinase pathways, and neuronal apoptosis were accessed on day 7 post-exposure. Our findings indicate that sevoflurane-induced cognitive deterioration in 3 × Tg mice, which was accompanied with the modulation of glutamate transporter, MAPK signaling, and neuronal apoptosis in the cortical and hippocampal regions. Meanwhile, no significant impact was observed in wild-type mice. Our results demonstrated that prolonged inhaled sevoflurane results in the exacerbation of neuronal and cognitive dysfunction which depends on the neuropathology background.
Assuntos
Doença de Alzheimer , Anestésicos Inalatórios , Síndromes Neurotóxicas , Doença de Alzheimer/metabolismo , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Anestésicos Inalatórios/efeitos adversos , Animais , Apoptose , Modelos Animais de Doenças , Hipocampo/metabolismo , Humanos , Camundongos , Síndromes Neurotóxicas/metabolismo , Sevoflurano/efeitos adversosRESUMO
AIMS: A variety of tissue clearing techniques have been developed to render intact tissue transparent. For thicker samples, additional partial tissue delipidation is required before immersion into the final refractive index (RI)-matching solution, which alone is often inadequate to achieve full tissue transparency. However, it is difficult to determine a sufficient degree of tissue delipidation, excess of which can result in tissue distortion and protein loss. Here, we aim to develop a clearing strategy that allows better monitoring and more precise determination of delipidation progress. METHODS: We combined the detergent sodium dodecyl sulphate (SDS) with OPTIClear, a RI-matching solution, to form a strategy termed Accurate delipidation with Optimal Clearing (Accu-OptiClearing). Accu-OptiClearing allows for a better preview of the final tissue transparency achieved when immersed in OPTIClear alone just before imaging. We assessed for the changes in clearing rate, protein loss, degree of tissue distortion, and preservation of antigens. RESULTS: Partial delipidation using Accu-OptiClearing accelerated tissue clearing and better preserved tissue structure and antigens than delipidation with SDS alone. Despite achieving similar transparency in the final OPTIClear solution, more lipids were retained in samples cleared with Accu-OptiClearing compared to SDS. CONCLUSIONS: Combining the RI-matching solution OPTIClear with detergents, Accu-OptiClearing, can avoid excessive delipidation, leading to accelerated tissue clearing, less tissue damage and better preserved antigens.
Assuntos
Encéfalo , Técnicas de Preparação Histocitológica/métodos , Imageamento Tridimensional/métodos , Animais , Artefatos , Feminino , Masculino , Camundongos , Microscopia Confocal/métodos , Ratos , Ratos Sprague-Dawley , Dodecilsulfato de Sódio , Tensoativos , Peixe-ZebraRESUMO
Ras-related C3 botulinum toxin substrate 1 (Rac1) is a member of the Rho family of GTPases that functions as a molecular switch to regulate many important cellular events including actin cytoskeleton remodeling during neurite outgrowth. Engulfment and cell motility 1 (ELMO1)-dedicator of cytokinesis 1 (DOCK180) is a bipartite guanine nucleotide exchange factor (GEF) complex that has been reported to activate Rac1 on the plasma membrane (PM). Emerging evidence suggests that the small GTPase ADP ribosylation factor 6 (ARF6) activates Rac1 via the ELMO1/DOCK180 complex. However, the exact mechanism by which ARF6 triggers ELMO1/DOCK180-mediated Rac1 signaling remains unclear. Here, we report that the neuronal scaffold protein FE65 serves as a functional link between ARF6 and ELMO1, allowing the formation of a multimeric signaling complex. Interfering with formation of this complex by transfecting either FE65-binding-defective mutants or FE65 siRNA attenuates both ARF6-ELMO1-mediated Rac1 activation and neurite elongation. Notably, the PM trafficking of ELMO1 is markedly decreased in cells with suppressed expression of either FE65 or ARF6. Likewise, this process is attenuated in the FE65-binding-defective mutants transfected cells. Moreover, overexpression of FE65 increases the amount of ELMO1 in the recycling endosome, an organelle responsible for returning proteins to the PM, whereas knockout of FE65 shows opposite effect. Together, our data indicates that FE65 potentiates ARF6-Rac1 signaling by orchestrating ARF6 and ELMO1 to promote the PM trafficking of ELMO1 via the endosomal recycling pathway, and thus, promotes Rac1-mediated neurite outgrowth.
Assuntos
Fatores de Ribosilação do ADP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuritos/metabolismo , Crescimento Neuronal/fisiologia , Neurônios/metabolismo , Proteínas Nucleares/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Fator 6 de Ribosilação do ADP , Animais , Células CHO , Células COS , Linhagem Celular , Membrana Celular/metabolismo , Chlorocebus aethiops , Cricetulus , Endossomos/metabolismo , Células HEK293 , Humanos , Transporte Proteico/fisiologia , Transdução de Sinais/fisiologiaRESUMO
Objectives: Endoplasmic reticulum (ER) stress is one of the key mechanisms contributing to Parkinson's disease (PD) pathology. Pathways triggered by ER stress are protective at early stages and initiate apoptosis when the damage is extensive. Methods: We have previously reported that oxyresveratrol rescues cells from oxidative stress and apoptosis in a cell culture model of PD. The aim of this study was to investigate whether the neuroprotective mechanism of oxyresveratrol extends to PD-associated ER stress. For this purpose, we employed two cellular models; to induce severe ER stress, Mes23.5 cells were treated with 6-hydroxydopamine (6-OHDA) and for ER stress driven by chaperones, human neuroblastoma cells were stably transfected to overexpress familial mutants of α-synuclein (α-syn). Results: Our results indicate that oxyresveratrol exhibits distinct modes of protection in both models. In the 6-OHDA model, it inhibited the transcription of activating transcription factor 4 (ATF4), which controls the fate of pro-apoptotic proteins. On the other hand, in the α-syn model, oxyresveratrol suppressed mutant A30P oligomer formation, thereby facilitating a reduction of the ER-chaperone, 78-kDa glucose-regulated protein (Grp78). Discussion: In summary, oxyresveratrol is protective against ER stress induced by two different triggers of PD. Owing to its wide range of defense mechanisms, oxyresveratrol is an ideal candidate for a multifactorial disease like PD.
Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Chaperona BiP do Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Transtornos Parkinsonianos/metabolismo , Extratos Vegetais/administração & dosagem , Estilbenos/administração & dosagem , Animais , Linhagem Celular Tumoral , Humanos , CamundongosRESUMO
A current bottleneck in the advance of neurophysics is the lack of reliable methods to quantitatively measure the interactions between neural cells and their microenvironment. Here, we present an experimental technique to probe the fundamental characteristics of neuron adhesion through repeated peeling of well-developed neurite branches on a substrate with an atomic force microscopy cantilever. At the same time, a total internal reflection fluorescence microscope is also used to monitor the activities of neural cell adhesion molecules (NCAMs) during detaching. It was found that NCAMs aggregate into clusters at the neurite-substrate interface, resulting in strong local attachment with an adhesion energy of â¼0.1 mJ/m2 and sudden force jumps in the recorded force-displacement curve. Furthermore, by introducing a healing period between two forced peelings, we showed that stable neurite-substrate attachment can be re-established in 2-5 min. These findings are rationalized by a stochastic model, accounting for the breakage and rebinding of NCAM-based molecular bonds along the interface, and provide new insights into the mechanics of neuron adhesion as well as many related biological processes including axon outgrowth and nerve regeneration.
Assuntos
Moléculas de Adesão de Célula Nervosa , Neuritos , Adesão Celular , Células Cultivadas , Moléculas de Adesão de Célula Nervosa/genética , Neurônios , TransfecçãoRESUMO
Emerging evidence suggests that sleep deprivation (SD) and circadian rhythm disruption (CRD) may interact and increase the risk for the development of Alzheimer's disease (AD). This review inspects different pathophysiological aspects of SD and CRD, and shows that the two may impair the glymphatic-vascular-lymphatic clearance of brain macromolecules (e.g., ß-amyloid and microtubule associated protein tau), increase local brain oxidative stress and diminish circulatory melatonin levels. Lastly, this review looks into the potential association between sleep and circadian rhythm with stress granule formation, which might be a new mechanism along the AD pathogenic pathway. In summary, SD and CRD is likely to be associated with a positive risk in developing Alzheimer's disease in humans.
Assuntos
Doença de Alzheimer/etiologia , Ritmo Circadiano/fisiologia , Sistema Glinfático , Melatonina/metabolismo , Estresse Oxidativo/fisiologia , Privação do Sono/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Sistema Glinfático/metabolismo , Sistema Glinfático/fisiopatologia , Humanos , Privação do Sono/complicaçõesRESUMO
BACKGROUND: Both human and animal studies have shown beneficial effects of physical exercise on brain health but most tend to be based on aerobic rather than resistance type regimes. Resistance exercise has the advantage of improving both muscular and cardiovascular function, both of which can benefit the frail and the elderly. However, the neuroprotective effects of resistance training in cognitive impairment are not well characterized. METHODS: We evaluated whether short-term resistant training could improve cognitive function and pathological changes in mice with pre-existing cognitive impairment. Nine-month-old 3xTg mouse underwent a resistance training protocol of climbing up a 1-m ladder with a progressively heavier weight loading. RESULTS: Compared with sedentary counterparts, resistance training improved cognitive performance and reduced neuropathological and neuroinflammatory changes in the frontal cortex and hippocampus of mice. In line with these results, inhibition of pro-inflammatory intracellular pathways was also demonstrated. CONCLUSIONS: Short-term resistance training improved cognitive function in 3xTg mice, and conferred beneficial effects on neuroinflammation, amyloid and tau pathology, as well as synaptic plasticity. Resistance training may represent an alternative exercise strategy for delaying disease progression in Alzheimer's disease.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Mediadores da Inflamação/metabolismo , Condicionamento Físico Animal/métodos , Condicionamento Físico Animal/psicologia , Treinamento Resistido/métodos , Doença de Alzheimer/terapia , Animais , Cognição/fisiologia , Inflamação/metabolismo , Inflamação/patologia , Inflamação/terapia , Mediadores da Inflamação/antagonistas & inibidores , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Transgênicos , Condicionamento Físico Animal/fisiologia , Fatores de TempoRESUMO
Damage-induced retraction of axons during traumatic brain injury is believed to play a key role in the disintegration of the neural network and to eventually lead to severe symptoms such as permanent memory loss and emotional disturbances. However, fundamental questions such as how axon retraction progresses and what physical factors govern this process still remain unclear. Here, we report a combined experimental and modeling study to address these questions. Specifically, a sharp atomic force microscope probe was used to transect axons and trigger their retraction in a precisely controlled manner. Interestingly, we showed that the retracting motion of a well-developed axon can be arrested by strong cell-substrate attachment. However, axon retraction was found to be retriggered if a second transection was conducted, albeit with a lower shrinking amplitude. Furthermore, disruption of the actin cytoskeleton or cell-substrate adhesion significantly altered the retracting dynamics of injured axons. Finally, a mathematical model was developed to explain the observed injury response of neural cells in which the retracting motion was assumed to be driven by the pre-tension in the axon and progress against neuron-substrate adhesion as well as the viscous resistance of the cell. Using realistic parameters, model predictions were found to be in good agreement with our observations under a variety of experimental conditions. By revealing the essential physics behind traumatic axon retraction, findings here could provide insights on the development of treatment strategies for axonal injury as well as its possible interplay with other neurodegenerative diseases.
Assuntos
Axônios/patologia , Citoesqueleto de Actina/metabolismo , Adesividade , Animais , Fenômenos Biomecânicos , Adesão Celular , Modelos Neurológicos , Ratos Sprague-Dawley , Imagem com Lapso de TempoRESUMO
Growing evidence has shown the beneficial influence of exercise on humans. Apart from classic cardioprotection, numerous studies have demonstrated that different exercise regimes provide a substantial improvement in various brain functions. Although the underlying mechanism is yet to be determined, emerging evidence for neuroprotection has been established in both humans and experimental animals, with most of the valuable findings in the field of mental health, neurodegenerative diseases, and acquired brain injuries. This review will discuss the recent findings of how exercise could ameliorate brain function in neuropathological states, demonstrated by either clinical or laboratory animal studies. Simultaneously, state-of-the-art molecular mechanisms underlying the exercise-induced neuroprotective effects and comparison between different types of exercise will be discussed in detail. A majority of reports show that physical exercise is associated with enhanced cognition throughout different populations and remains as a fascinating area in scientific research because of its universal protective effects in different brain domain functions. This article is to review what we know about how physical exercise modulates the pathophysiological mechanisms of neurodegeneration.
Assuntos
Encefalopatias/terapia , Encéfalo/fisiologia , Terapia por Exercício , Exercício Físico/fisiologia , Doenças Neurodegenerativas/terapia , Animais , Humanos , Transtornos Mentais/terapia , Doenças Neurodegenerativas/metabolismo , Condicionamento Físico Animal/fisiologiaRESUMO
Persistent inflammation in the systemic immune system can impose detrimental effects on the central nervous system (CNS). Neuroinflammation might be a result of this to accelerate the progressive deterioration of neuronal functions during aging. In this regard, controlling inflammation through delaying and/or preventing chronic inflammatory diseases may be a potential strategy to prevent or modify the progression of Alzheimer's Disease (AD). Periodontitis is a chronic inflammatory disease of the oral cavity that is common among the elderly, especially for those who have decline in cognitive functions. While epidemiological findings support the association of chronic periodontitis and cognitive decline, whether they have causal relationship remains unclear. Nonetheless, the possibility that periodontopathogens, systemic immune cells and inflammatory cytokines could reach the CNS should not be overlooked. The impacts of periodontitis on CNS homeostasis and inflammation as a pathophysiological factor concerning the association between periodontitis and AD will be discussed in this review. Future work should elucidate the pathological pathways involved in periodontitis-induced cerebral infections and inflammation, and define the role of the latter in AD progression.
Assuntos
Periodontite Crônica/imunologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/imunologia , Idoso , Doença de Alzheimer/metabolismo , Barreira Hematoencefálica/imunologia , Doença Crônica , Periodontite Crônica/fisiopatologia , Cognição/fisiologia , Disfunção Cognitiva/complicações , Citocinas/imunologia , Progressão da Doença , Humanos , Inflamação/complicações , Neuroimunomodulação/imunologia , Fatores de RiscoRESUMO
Although the dynamic response of neurites is believed to play crucial roles in processes like axon outgrowth and formation of the neural network, the dynamic mechanical properties of such protrusions remain poorly understood. In this study, by using AFM (atomic force microscopy) indentation, we systematically examined the dynamic behavior of well-developed neurites on primary neurons under different loading modes (step loading, oscillating loading and ramp loading). Interestingly, the response was found to be strongly rate-dependent, with an apparent initial and long-term elastic modulus around 800 and 80 Pa, respectively. To better analyze the measurement data and extract information of key interest, the finite element simulation method (FEM) was also conducted where the neurite was treated as a viscoelastic solid consisting of multiple characteristic relaxation times. It was found that a minimum of three relaxation timescales, i.e. â¼0.01, 0.1 and 1 seconds, are needed to explain the observed relaxation curve as well as fit simulation results to the indentation and rheology data under different loading rates and driving frequencies. We further demonstrated that these three characteristic relaxation times likely originate from the thermal fluctuations of the microtubule, membrane relaxation and cytosol viscosity, respectively. By identifying key parameters describing the time-dependent behavior of neurites, as well as revealing possible physical mechanisms behind, this study could greatly help us understand how neural cells perform their biological duties over a wide spectrum of timescales.
Assuntos
Microscopia de Força Atômica/métodos , Neuritos/fisiologia , Reologia/métodos , Animais , Fenômenos Biomecânicos , Células Cultivadas , Simulação por Computador , Módulo de Elasticidade , Análise de Elementos Finitos , Cinética , Modelos Biológicos , Neuritos/ultraestrutura , Ratos Sprague-Dawley , Estresse MecânicoRESUMO
BACKGROUND: Systemic inflammation induces neuroinflammation and cellular changes such as tau phosphorylation to impair cognitive function, including learning and memory. This study uses a single model, laparotomy without any pathogen, to characterize these changes and their responses to anti-inflammatory treatment in the intermediate term. METHODS: In a two-part experiment, wild-type C57BL/6N mice (male, 3 month old, 25 ± 2 g) were subjected to sevoflurane anesthesia alone or to a laparotomy. Cognitive performance, systemic and neuroinflammatory responses, and tau phosphorylation were evaluated on postoperative days (POD) 1, 3, and 14. The effect of perioperative ibuprofen intervention (60 mg/kg) on these changes was then assessed. RESULTS: Mice in the laparotomy group displayed memory impairment up to POD 14 with initial high levels of inflammatory cytokines in the liver, frontal cortex (IL-1ß, IL-6, and TNF-α), and hippocampus (IL-1ß and IL-8). On POD 14, although most circulating and resident cytokine levels returned to normal, a significant number of microglia and astrocytes remained activated in the frontal cortex and microglia in the hippocampus, as well as abnormal tau phosphorylation in these two brain regions. Perioperative ibuprofen improved cognitive performance, attenuated systemic inflammation and glial activation, and suppressed the abnormal tau phosphorylation both in the frontal cortex and hippocampus. CONCLUSIONS: Our results suggest that (1) cognitive dysfunction is associated with an unbalanced pro-inflammatory and anti-inflammatory response, tauopathy, and gliosis; (2) cognitive dysfunction, gliosis, and tauopathy following laparotomy can persist well beyond the immediate postoperative period; and (3) anti-inflammatory drugs can act rapidly to attenuate inflammatory responses in the brain and negatively modulate neuropathological changes to improve cognition. These findings may have implications for the duration of therapeutic strategies aimed at curtaining cognitive dysfunction following surgery.
Assuntos
Citocinas/metabolismo , Encefalite/etiologia , Regulação da Expressão Gênica/fisiologia , Transtornos da Memória/etiologia , Complicações Pós-Operatórias/patologia , Complicações Pós-Operatórias/fisiopatologia , Anestésicos Inalatórios/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio , Citocinas/genética , Modelos Animais de Doenças , Encefalite/tratamento farmacológico , Comportamento Exploratório/efeitos dos fármacos , Laparotomia/efeitos adversos , Fígado/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Complicações Pós-Operatórias/imunologia , Sevoflurano/farmacologia , Proteínas tau/metabolismoRESUMO
BACKGROUND: Silica nanoparticles (SiO2-NPs) are naturally enriched and broadly utilized in the manufacturing industry. While previous studies have demonstrated toxicity in neuronal cell lines after SiO2-NPs exposure, the role of SiO2-NPs in neurodegeneration is largely unknown. Here, we evaluated the effects of SiO2-NPs-exposure on behavior, neuropathology, and synapse in young adult mice and primary cortical neuron cultures. RESULTS: Male C57BL/6 N mice (3 months old) were exposed to either vehicle (sterile PBS) or fluorescein isothiocyanate (FITC)-tagged SiO2-NPs (NP) using intranasal instillation. Behavioral tests were performed after 1 and 2 months of exposure. We observed decreased social activity at both time points as well as anxiety and cognitive impairment after 2 months in the NP-exposed mice. NP deposition was primarily detected in the medial prefrontal cortex and the hippocampus. Neurodegeneration-like pathological changes, including reduced Nissl staining, increased tau phosphorylation, and neuroinflammation, were also present in the brains of NP-exposed mice. Furthermore, we observed NP-induced impairment in exocytosis along with decreased synapsin I and increased synaptophysin expression in the synaptosome fractions isolated from the frontal cortex as well as primary neuronal cultures. Extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were also activated in the frontal cortex of NP-exposed mice. Moreover, inhibition of ERK activation prevented NP-mediated changes in exocytosis in cultured neurons, highlighting a key role in the changes induced by NP exposure. CONCLUSIONS: Intranasal instillation of SiO2-NPs results in mood dysfunction and cognitive impairment in young adult mice and causes neurodegeneration-like pathology and synaptic changes via ERK activation.
Assuntos
Comportamento Animal/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Nanopartículas/toxicidade , Neurônios/efeitos dos fármacos , Dióxido de Silício/toxicidade , Sinapses/efeitos dos fármacos , Animais , Exocitose/efeitos dos fármacos , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Camundongos Endogâmicos C57BL , Neurônios/patologia , Tamanho da Partícula , Propriedades de Superfície , Sinapses/enzimologia , Sinapses/patologiaRESUMO
Sleep disorders are among the most common clinical problems and possess a significant concern for the geriatric population. More importantly, while around 40% of elderly adults have sleep-related complaints, sleep disorders are more frequently associated with co-morbidities including age-related neurodegenerative diseases and mild cognitive impairment. Recently, increasing evidence has indicated that disturbed sleep may not only serve as the consequence of brain atrophy, but also contribute to the pathogenesis of dementia and, therefore, significantly increase dementia risk. Since the current therapeutic interventions lack efficacies to prevent, delay or reverse the pathological progress of dementia, a better understanding of underlying mechanisms by which sleep disorders interact with the pathogenesis of dementia will provide possible targets for the prevention and treatment of dementia. In this review, we briefly describe the physiological roles of sleep in learning/memory, and specifically update the recent research evidence demonstrating the association between sleep disorders and dementia. Plausible mechanisms are further discussed. Moreover, we also evaluate the possibility of sleep therapy as a potential intervention for dementia.