Iron is an essential component of oxidative metabolism and a cofactor for a variety of enzymes. Because of its chemical properties as a transition metal, iron can serve both as an electron donor and acceptor and, as s...Iron is an essential component of oxidative metabolism and a cofactor for a variety of enzymes. Because of its chemical properties as a transition metal, iron can serve both as an electron donor and acceptor and, as such, excess levels of free iron are toxic. Given this potential for toxicity, a number of pro- teins, including transferrin, transferrin receptor, and ferritin, tightly control iron transport, uptake, and storage in the central nervous system. Patients with Parkinson＇s disease （PD） show a dramatic increase in iron content in dopaminergic neurons of the substantia nizra,展开更多
Neuropsychiatric disorders(NPDs) constitute a heavyburden on public health systems around the world and studies have demonstrated that the negative impact of NPDs is larger in Low and Middle Income Countries(LMICs). I...Neuropsychiatric disorders(NPDs) constitute a heavyburden on public health systems around the world and studies have demonstrated that the negative impact of NPDs is larger in Low and Middle Income Countries(LMICs). In recent decades, several studies have come to the understanding that genetic factors play a major role in the risk for a large number of NPDs. However, few neuropsychiatric genetics studies have been published from LMICs. In this Editorial, we discuss important issues impinging on advances in neuropsychiatric genetics research in LMICs. It is essential that scientists educate policymakers and officials of funding agencies on the importance of providing adequate funding for research in these areas. Development of local well-supported research programs focused on NPD genetics should be an important asset to develop; it would facilitate the establishment of sustainable research efforts that could lead to appropriate diagnosis and specific, affordable and feasible interventions in LMICs. It is important to point out that research into the biological basis of human NPDs is not only an academic effort reserved for a few elite institutions in economically developed countries, but it is vitally important for the mental health of people around the world.展开更多
Adipocyte-derived leptin is a pleiotropic hormone implicated in control of lipid storage and mobilization, bone homeostasis, immune function and neuronal plasticity. Leptin has been shown to prevent accumulation of ex...Adipocyte-derived leptin is a pleiotropic hormone implicated in control of lipid storage and mobilization, bone homeostasis, immune function and neuronal plasticity. Leptin has been shown to prevent accumulation of extracellular Aβ and hyperphosphorylation of tau in both cell culture and animal models. Herein an investigation was undertaken to test leptin’s ability to prevent the exacerbation/activation of AD-related pathways in neurons following their exposure to a high concentration of a variety of lipids. Specifically, cholesterol, oleic acid and/or ceramide were added to the media of cells resulting in decreased cellular viability and energy metabolism, and in increased tau phosphorylation and extracellular Aβ. Leptin increased viability, boosted cellular metabolism by activating AMP-activated protein kinase (AMPK) and the sirtuins (SIRT) and reduced tau phosphorylation and Aβ accumulation in a dose-dependent manner in response to select challenges. These findings demonstrate that leptin can attenuate the harmful effect of certain lipids that lead to exacerbation or activation of AD pathways. The study herein also provides the basis for a novel screening platform to define and identify a novel class of “metabolic” compounds addressing Alzheimer’s disease, based on a biological profile similar to leptin.展开更多
Understanding the mechanism of oxidative stress is likely to yield new insights regarding the pathogenesis of Alzheimer’s disease (AD). Our earlier work focused on the difference between hemoglobin and methemoglobin ...Understanding the mechanism of oxidative stress is likely to yield new insights regarding the pathogenesis of Alzheimer’s disease (AD). Our earlier work focused on the difference between hemoglobin and methemoglobin degradation, respectively leading to ferrous (Fe2+) iron, or ferric (Fe3+) iron. Methemoglobin has the role of carrier, the donor of cytotoxic and redox-active ferric (Fe3+) iron, which can directly accumulate and increase the rate of capillary endothelial cell apoptosis, and may cross into the brain parenchyma, to the astrocytes, glia, neurons, and other neuronal cells (neurovascular unit). This supposition helps us to understand the transport and neuronal accumulation process of ferric iron, and determine how iron is transported and accumulated intracellularly, identifiable as “Brain rust”. Earlier research found that the incidences of neonatal jaundice (p = 0.034), heart murmur (p = 0.011) and disorders such as dyslalia and learning/memory impairments (p = 0.002) were significantly higher in those children born from mothers with methemoglobinemia. Our hypothesis suggests that prenatal iron abnormalities could lead to greater neuronal death, the disease ageing process, and neurodegenerative disorders such as AD and other neurodegenerative diseases.展开更多
Considerable debate and controversy surround the cause（s） of AIzheimer＇s disease （AD）. To date, several theories have gained notoriety, however none is universally accepted. In this review, we provide evidence fo...Considerable debate and controversy surround the cause（s） of AIzheimer＇s disease （AD）. To date, several theories have gained notoriety, however none is universally accepted. In this review, we provide evidence for the oxidative stress-induced AD cascade that posits aged mitochondria as the critical origin of neurodegeneration in AD.展开更多
Amyotrophic lateral sclerosis(ALS)is the most common motor neuron disease characterized by progressive loss of motor neurons in the brainstem and spinal cord.Currently,there is no cure or effective treatment for ALS a...Amyotrophic lateral sclerosis(ALS)is the most common motor neuron disease characterized by progressive loss of motor neurons in the brainstem and spinal cord.Currently,there is no cure or effective treatment for ALS and the cause of disease is unknown in the majority of ALS cases.Neuronal mitochondria dysfunction is one of the earliest features of ALS.Mitochondria are highly dynamic organelles that undergo continuous fission,fusion,trafficking and turnover,all of which contribute to the maintenance of mitochondrial function.Abnormal mitochondrial dynamics have been repeatedly reported in ALS and increasing evidence suggests altered mitochondrial dynamics as possible pathomechanisms underlying mitochondrial dysfunction in ALS.Here,we provide an overview of mitochondrial dysfunction and dynamic abnormalities observed in ALS,and discuss the possibility of targeting mitochondrial dynamics as a novel therapeutic approach for ALS.展开更多
Background:In Alzheimer disease(AD),hyperphosphorylation of tau proteins results in microtubule destabilization and cytoskeletal abnormalities.Our prior ultra-morphometric studies documented a clear reduction in micro...Background:In Alzheimer disease(AD),hyperphosphorylation of tau proteins results in microtubule destabilization and cytoskeletal abnormalities.Our prior ultra-morphometric studies documented a clear reduction in microtubules in pyramidal neurons in AD compared to controls,however,this reduction did not coincide with the presence of paired helical filaments.The latter suggests the presence of compensatory mechanism(s)that stabilize microtubule dynamics despite the loss of tau binding and stabilization.Microtubules are composed of tubulin dimers which are subject to posttranslational modifications that affect the stability and function of microtubules.Methods:In this study,we performed a detailed analysis on changes in the posttranslational modifications in tubulin in postmortem human brain tissues from AD patients and age-matched controls by immunoblot and immunocytochemistry.Results:Consistent with our previous study,we found decreased levels ofα-tubulin in AD brain.Levels of tubulin with various posttranslational modifications such as polyglutamylation,tyrosination,and detyrosination were also proportionally reduced in AD brain,but,interestingly,there was an increase in the proportion of the acetylatedα-tubulin in the remainingα-tubulin.Tubulin distribution was changed from predominantly in the processes to be more accumulated in the cell body.The number of processes containing polyglutamylated tubulin was well preserved in AD neurons.While there was a cell autonomous detrimental effect of NFTs on tubulin,this is likely a gradual and slow process,and there was no selective loss of acetylated or polyglutamylated tubulin in NFT-bearing neurons.Conclusions:Overall,we suggest that the specific changes in tubulin modification in AD brain likely represent a compensatory response.展开更多
文摘Iron is an essential component of oxidative metabolism and a cofactor for a variety of enzymes. Because of its chemical properties as a transition metal, iron can serve both as an electron donor and acceptor and, as such, excess levels of free iron are toxic. Given this potential for toxicity, a number of pro- teins, including transferrin, transferrin receptor, and ferritin, tightly control iron transport, uptake, and storage in the central nervous system. Patients with Parkinson＇s disease （PD） show a dramatic increase in iron content in dopaminergic neurons of the substantia nizra,
基金Supported by Research grants from VCTI-UAN and Colcienciasresearch grants from Universidad del Rosario
文摘Neuropsychiatric disorders(NPDs) constitute a heavyburden on public health systems around the world and studies have demonstrated that the negative impact of NPDs is larger in Low and Middle Income Countries(LMICs). In recent decades, several studies have come to the understanding that genetic factors play a major role in the risk for a large number of NPDs. However, few neuropsychiatric genetics studies have been published from LMICs. In this Editorial, we discuss important issues impinging on advances in neuropsychiatric genetics research in LMICs. It is essential that scientists educate policymakers and officials of funding agencies on the importance of providing adequate funding for research in these areas. Development of local well-supported research programs focused on NPD genetics should be an important asset to develop; it would facilitate the establishment of sustainable research efforts that could lead to appropriate diagnosis and specific, affordable and feasible interventions in LMICs. It is important to point out that research into the biological basis of human NPDs is not only an academic effort reserved for a few elite institutions in economically developed countries, but it is vitally important for the mental health of people around the world.
文摘Adipocyte-derived leptin is a pleiotropic hormone implicated in control of lipid storage and mobilization, bone homeostasis, immune function and neuronal plasticity. Leptin has been shown to prevent accumulation of extracellular Aβ and hyperphosphorylation of tau in both cell culture and animal models. Herein an investigation was undertaken to test leptin’s ability to prevent the exacerbation/activation of AD-related pathways in neurons following their exposure to a high concentration of a variety of lipids. Specifically, cholesterol, oleic acid and/or ceramide were added to the media of cells resulting in decreased cellular viability and energy metabolism, and in increased tau phosphorylation and extracellular Aβ. Leptin increased viability, boosted cellular metabolism by activating AMP-activated protein kinase (AMPK) and the sirtuins (SIRT) and reduced tau phosphorylation and Aβ accumulation in a dose-dependent manner in response to select challenges. These findings demonstrate that leptin can attenuate the harmful effect of certain lipids that lead to exacerbation or activation of AD pathways. The study herein also provides the basis for a novel screening platform to define and identify a novel class of “metabolic” compounds addressing Alzheimer’s disease, based on a biological profile similar to leptin.
文摘Understanding the mechanism of oxidative stress is likely to yield new insights regarding the pathogenesis of Alzheimer’s disease (AD). Our earlier work focused on the difference between hemoglobin and methemoglobin degradation, respectively leading to ferrous (Fe2+) iron, or ferric (Fe3+) iron. Methemoglobin has the role of carrier, the donor of cytotoxic and redox-active ferric (Fe3+) iron, which can directly accumulate and increase the rate of capillary endothelial cell apoptosis, and may cross into the brain parenchyma, to the astrocytes, glia, neurons, and other neuronal cells (neurovascular unit). This supposition helps us to understand the transport and neuronal accumulation process of ferric iron, and determine how iron is transported and accumulated intracellularly, identifiable as “Brain rust”. Earlier research found that the incidences of neonatal jaundice (p = 0.034), heart murmur (p = 0.011) and disorders such as dyslalia and learning/memory impairments (p = 0.002) were significantly higher in those children born from mothers with methemoglobinemia. Our hypothesis suggests that prenatal iron abnormalities could lead to greater neuronal death, the disease ageing process, and neurodegenerative disorders such as AD and other neurodegenerative diseases.
基金supported by the National Institutes of Health(NS083385-01)the Alzheimer’s Association(IIRG-10-173358 and IIRG-10-173471)
文摘Considerable debate and controversy surround the cause（s） of AIzheimer＇s disease （AD）. To date, several theories have gained notoriety, however none is universally accepted. In this review, we provide evidence for the oxidative stress-induced AD cascade that posits aged mitochondria as the critical origin of neurodegeneration in AD.
基金by grants from National Institutes of Health(R03AG044680,R21NS085747 and R01NS089604)Alzheimer’s Association(2014-NIRG-301299).
文摘Amyotrophic lateral sclerosis(ALS)is the most common motor neuron disease characterized by progressive loss of motor neurons in the brainstem and spinal cord.Currently,there is no cure or effective treatment for ALS and the cause of disease is unknown in the majority of ALS cases.Neuronal mitochondria dysfunction is one of the earliest features of ALS.Mitochondria are highly dynamic organelles that undergo continuous fission,fusion,trafficking and turnover,all of which contribute to the maintenance of mitochondrial function.Abnormal mitochondrial dynamics have been repeatedly reported in ALS and increasing evidence suggests altered mitochondrial dynamics as possible pathomechanisms underlying mitochondrial dysfunction in ALS.Here,we provide an overview of mitochondrial dysfunction and dynamic abnormalities observed in ALS,and discuss the possibility of targeting mitochondrial dynamics as a novel therapeutic approach for ALS.
基金by NIH grant NS083385(to X.Z.)and by Alzheimer Association grant IIRG-13-284849(to GP)by Chinese Overseas,Hong Kong and Macao Scholars Collaborated Research Fund Grant 81228007 to X.Z.by the Dr.Robert M.Kohrman Memorial Fund.
文摘Background:In Alzheimer disease(AD),hyperphosphorylation of tau proteins results in microtubule destabilization and cytoskeletal abnormalities.Our prior ultra-morphometric studies documented a clear reduction in microtubules in pyramidal neurons in AD compared to controls,however,this reduction did not coincide with the presence of paired helical filaments.The latter suggests the presence of compensatory mechanism(s)that stabilize microtubule dynamics despite the loss of tau binding and stabilization.Microtubules are composed of tubulin dimers which are subject to posttranslational modifications that affect the stability and function of microtubules.Methods:In this study,we performed a detailed analysis on changes in the posttranslational modifications in tubulin in postmortem human brain tissues from AD patients and age-matched controls by immunoblot and immunocytochemistry.Results:Consistent with our previous study,we found decreased levels ofα-tubulin in AD brain.Levels of tubulin with various posttranslational modifications such as polyglutamylation,tyrosination,and detyrosination were also proportionally reduced in AD brain,but,interestingly,there was an increase in the proportion of the acetylatedα-tubulin in the remainingα-tubulin.Tubulin distribution was changed from predominantly in the processes to be more accumulated in the cell body.The number of processes containing polyglutamylated tubulin was well preserved in AD neurons.While there was a cell autonomous detrimental effect of NFTs on tubulin,this is likely a gradual and slow process,and there was no selective loss of acetylated or polyglutamylated tubulin in NFT-bearing neurons.Conclusions:Overall,we suggest that the specific changes in tubulin modification in AD brain likely represent a compensatory response.
