Showing papers by "Mark P. Mattson published in 2008"
TL;DR: Emerging knowledge of the actions of Ca(2+) upstream and downstream of Abeta provides opportunities to develop novel preventative and therapeutic interventions for AD.
795 citations
TL;DR: It is shown that individual mitochondria undergo spontaneous bursts of superoxide generation, termed "superoxide flashes", and proposed that superoxide flashes could serve as a valuable biomarker for a wide variety of oxidative stress-related diseases.
679 citations
TL;DR: It is concluded that a high‐calorie diet reduces hippocampal synaptic plasticity and impairs cognitive function, possibly through BDNF‐mediated effects on dendritic spines.
Abstract: Overall dietary energy intake, particularly the consumption of simple sugars such as fructose, has been increasing steadily in Western societies, but the effects of such diets on the brain are poorly understood. Here, we used functional and structural assays to characterize the effects of excessive caloric intake on the hippocampus, a brain region important for learning and memory. Rats fed with a high-fat, high-glucose diet supplemented with high-fructose corn syrup showed alterations in energy and lipid metabolism similar to clinical diabetes, with elevated fasting glucose and increased cholesterol and triglycerides. Rats maintained on this diet for 8 months exhibited impaired spatial learning ability, reduced hippocampal dendritic spine density, and reduced long-term potentiation at Schaffer collateral--CA1 synapses. These changes occurred concurrently with reductions in levels of brain-derived neurotrophic factor in the hippocampus. We conclude that a high-calorie diet reduces hippocampal synaptic plasticity and impairs cognitive function, possibly through BDNF-mediated effects on dendritic spines.
655 citations
TL;DR: It is demonstrated that, in both insulin-deficient rats and insulin-resistant mice, diabetes impairs hippocampus-dependent memory, perforant path synaptic plasticity and adult neurogenesis, and the adrenal steroid corticosterone contributes to these adverse effects.
Abstract: Many organ systems are adversely affected by diabetes, including the brain, which undergoes changes that may increase the risk of cognitive decline. Although diabetes influences the hypothalamic-pituitary-adrenal axis, the role of this neuroendocrine system in diabetes-induced cognitive dysfunction remains unexplored. Here we demonstrate that, in both insulin-deficient rats and insulin-resistant mice, diabetes impairs hippocampus-dependent memory, perforant path synaptic plasticity and adult neurogenesis, and the adrenal steroid corticosterone contributes to these adverse effects. Rats treated with streptozocin have reduced insulin and show hyperglycemia, increased corticosterone, and impairments in hippocampal neurogenesis, synaptic plasticity and learning. Similar deficits are observed in db/db mice, which are characterized by insulin resistance, elevated corticosterone and obesity. Changes in hippocampal plasticity and function in both models are reversed when normal physiological levels of corticosterone are maintained, suggesting that cognitive impairment in diabetes may result from glucocorticoid-mediated deficits in neurogenesis and synaptic plasticity.
556 citations
TL;DR: By enhancing neurotrophic factor signaling, environmental factors such as exercise and dietary energy restriction, and chemicals such as antidepressants may optimize glutamatergic signaling and protect against neurological disorders.
Abstract: Glutamate’s role as a neurotransmitter at synapses has been known for 40 years, but glutamate has since been shown to regulate neurogenesis, neurite outgrowth, synaptogenesis and neuron survival in the developing and adult mammalian nervous system. Cell surface glutamate receptors are coupled to Ca2+ influx and release from endoplasmic reticulum stores which causes rapid (kinase- and protease-mediated) and delayed (transcription-dependent) responses that change the structure and function of neurons. Neurotrophic factors and glutamate interact to regulate developmental and adult neuroplasticity. For example, glutamate stimulates the production of brain-derived neurotrophic factor (BDNF) which, in turn, modifies neuronal glutamate sensitivity, Ca2+ homeostasis and plasticity. Neurotrophic factors may modify glutamate signalling directly, by changing the expression of glutamate receptor subunits and Ca2+-regulating proteins, and also indirectly by inducing the production of antioxidant enzymes, energy-regulating proteins and anti-apoptotic Bcl2 family members. Excessive activation of glutamate receptors, under conditions of oxidative and metabolic stress, may contribute to neuronal dysfunction and degeneration in diseases ranging from stroke and Alzheimer’s disease to psychiatric disorders. By enhancing neurotrophic factor signalling, environmental factors such as exercise and dietary energy restriction, and chemicals such as antidepressants may optimize glutamatergic signalling and protect against neurological disorders.
555 citations
TL;DR: It is demonstrated that severe ischemic AKI induces inflammation and functional changes in the brain and targeting these pathways could reduce morbidity and mortality in critically ill patients with severe AKI.
Abstract: Although neurologic sequelae of acute kidney injury (AKI) are well described, the pathogenesis of acute uremic encephalopathy is poorly understood. This study examined the short-term effect of ischemic AKI on inflammatory and functional changes of the brain in mice by inducing bilateral renal ischemia for 60 min and studying the brains 24 h later. Compared with sham mice, mice with AKI had increased neuronal pyknosis and microgliosis in the brain. AKI also led to increased levels of the proinflammatory chemokines keratinocyte-derived chemoattractant and G-CSF in the cerebral cortex and hippocampus and increased expression of glial fibrillary acidic protein in astrocytes in the cortex and corpus callosum. In addition, extravasation of Evans blue dye into the brain suggested that the blood-brain barrier was disrupted in mice with AKI. Because liver failure also leads to encephalopathy, ischemic liver injury was induced in mice with normal renal function; neuronal pyknosis and glial fibrillary acidic protein expression were not increased, suggesting differential effects on the brain depending on the organ injured. For evaluation of the effects of AKI on brain function, locomotor activity was studied using an open field test. Mice subjected to renal ischemia or bilateral nephrectomy had moderate to severe declines in locomotor activity compared with sham-operated mice. These data demonstrate that severe ischemic AKI induces inflammation and functional changes in the brain. Targeting these pathways could reduce morbidity and mortality in critically ill patients with severe AKI.
334 citations
TL;DR: It is suggested that curcumin can stimulate developmental and adult hippocampal neurogenesis, and a biological activity that may enhance neural plasticity and repair is suggested.
317 citations
TL;DR: The hormesis hypothesis of phytochemical actions with a focus on the Nrf2/ARE signaling pathway is described as a prototypical example of a neuroprotective mechanism of action of specific dietary phytochemicals.
Abstract: Compelling evidence from epidemiological studies suggests beneficial roles of dietary phytochemicals in protecting against chronic disorders such as cancer, and inflammatory and cardiovascular diseases. Emerging findings suggest that several dietary phytochemicals also benefit the nervous system and, when consumed regularly, may reduce the risk of disorders such as Alzheimer’s and Parkinson’s diseases. The evidence supporting health benefits of vegetables and fruits provide a rationale for identification of the specific phytochemicals responsible, and for investigation of their molecular and cellular mechanisms of action. One general mechanism of action of phytochemicals that is emerging from recent studies is that they activate adaptive cellular stress response pathways. From an evolutionary perspective, the noxious properties of such phytochemicals play an important role in dissuading insects and other pests from eating the plants. However at the subtoxic doses ingested by humans that consume the plants, the phytochemicals induce mild cellular stress responses. This phenomenon has been widely observed in biology and medicine, and has been described as ‘preconditioning’ or ‘hormesis.’ Hormetic pathways activated by phytochemicals may involve kinases and transcription factors that induce the expression of genes that encode antioxidant enzymes, protein chaperones, phase-2 enzymes, neurotrophic factors, and other cytoprotective proteins. Specific examples of such pathways include the sirtuin–FOXO pathway, the NF-κB pathway, and the Nrf-2/ARE pathway. In this article, we describe the hormesis hypothesis of phytochemical actions with a focus on the Nrf2/ARE signaling pathway as a prototypical example of a neuroprotective mechanism of action of specific dietary phytochemicals.
315 citations
TL;DR: New findings suggest that several heavily studied phytochemicals exhibit biphasic dose responses on cells with low doses activating signaling pathways that result in increased expression of genes encoding cytoprotective proteins including antioxidant enzymes, protein chaperones, growth factors and mitochondrial proteins.
267 citations
TL;DR: It is reported that glucagon‐like peptide‐1 (GLP‐1) signaling in taste buds modulates taste sensitivity in behaving mice, and this findings suggest a novel paracrine mechanism for the regulation of taste function.
Abstract: In many sensory systems, stimulus sensitivity is dynamically modulated through mechanisms of peripheral adaptation, efferent input, or hormonal action. In this way, responses to sensory stimuli can be optimized in the context of both the environment and the physiological state of the animal. Although the gustatory system critically influences food preference, food intake and metabolic homeostasis, the mechanisms for modulating taste sensitivity are poorly understood. In this study, we report that glucagon-like peptide-1 (GLP-1) signaling in taste buds modulates taste sensitivity in behaving mice. We find that GLP-1 is produced in two distinct subsets of mammalian taste cells, while the GLP-1 receptor is expressed on adjacent intragemmal afferent nerve fibers. GLP-1 receptor knockout mice show dramatically reduced taste responses to sweeteners in behavioral assays, indicating that GLP-1 signaling normally acts to maintain or enhance sweet taste sensitivity. A modest increase in citric acid taste sensitivity in these knockout mice suggests GLP-1 signaling may modulate sour taste, as well. Together, these findings suggest a novel paracrine mechanism for the regulation of taste function.
258 citations
TL;DR: It is found that female 3xTg-AD transgenic mice expressing mutant APP, presenilin-1 and tau have significantly more aggressive Abeta pathology, and this suggests that a combination of increased Abeta production and decreased Abeta degradation may contribute to higher risk of AD in females.
TL;DR: Laminin is defined as a key ECM molecule to enhance neural progenitor generation, expansion and differentiation into neurons from hESCs and the cell-laminin interactions involve α6β1 integrin receptors implicating a possible role of laminin/α6β 1 integrin signaling in directed neural differentiation of hESC.
Abstract: Interactions of cells with the extracellular matrix (ECM) are critical for the establishment and maintenance of stem cell self-renewal and differentiation. However, the ECM is a complex mixture of matrix molecules; little is known about the role of ECM components in human embryonic stem cell (hESC) differentiation into neural progenitors and neurons. A reproducible protocol was used to generate highly homogenous neural progenitors or a mixed population of neural progenitors and neurons from hESCs. This defined adherent culture system allowed us to examine the effect of ECM molecules on neural differentiation of hESCs. hESC-derived differentiating embryoid bodies were plated on Poly-D-Lysine (PDL), PDL/fibronectin, PDL/laminin, type I collagen and Matrigel, and cultured in neural differentiation medium. We found that the five substrates instructed neural progenitors followed by neuronal differentiation to differing degrees. Glia did not appear until 4 weeks later. Neural progenitor and neuronal generation and neurite outgrowth were significantly greater on laminin and laminin-rich Matrigel substrates than on other 3 substrates. Laminin stimulated hESC-derived neural progenitor expansion and neurite outgrowth in a dose-dependent manner. The laminin-induced neural progenitor expansion was partially blocked by the antibody against integrin α6 or β1 subunit. We defined laminin as a key ECM molecule to enhance neural progenitor generation, expansion and differentiation into neurons from hESCs. The cell-laminin interactions involve α6β1 integrin receptors implicating a possible role of laminin/α6β1 integrin signaling in directed neural differentiation of hESCs. Since laminin acts in concert with other ECM molecules in vivo, evaluating cellular responses to the composition of the ECM is essential to clarify further the role of cell-matrix interactions in neural derivation of hESCs.
TL;DR: It is reported that TLR4 expression increases in neurons when exposed to amyloid beta-peptide (Abeta1-42) or the lipid peroxidation product 4-hydroxynonenal (HNE), and this finding is identified as a potential therapeutic target for AD.
TL;DR: It is reported that primary hippocampal neurons from PS1 mutant knock-in mice, which express the human PS1M146V mutation at normal levels, exhibit increased vulnerability to amyloid beta-peptide toxicity.
Abstract: : Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS1) gene. Overexpression of PS1 mutations in cultured PC12 cells increases their vulnerability to apoptosis-induced trophic factor withdrawal and oxidative insults. We now report that primary hippocampal neurons from PS1 mutant knock-in mice, which express the human PS1M146V mutation at normal levels, exhibit increased vulnerability to amyloid β-peptide toxicity. The endangering action of mutant PS1 was associated with increased superoxide production, mitochondrial membrane depolarization, and caspase activation. The peroxynitrite-scavenging antioxidant uric acid and the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone protected hippocampal neurons expressing mutant PS1 against cell death induced by amyloid β-peptide. Increase oxidative stress may contribute to the pathogenic action of PS1 mutations, and antioxidants may counteract the adverse property of such AD-linked mutations.
TL;DR: It is shown that both embryonic and adult hippocampal neurons express leptin receptors coupled to activation of STAT3 and phosphatidylinositol 3-kinase-Akt signaling pathways, suggesting that leptin signaling serves a neurotrophic function in the developing and adult hippocampus
TL;DR: This work reviews the current literature on the hypothalamic-pituitary-adrenal (HPA) axis regulation by wheel running, a voluntary and controllable stressor with a distinct temporal profile and proposes mechanisms to reduce the reactivity to this stressor.
Abstract: Stress exerts complex effects on the brain and periphery, dependent on the temporal profile and intensity of the stressor. The consequences of a stressful event can also be determined by other characteristics of the stressor, such as whether it is predictable and controllable. While the traditional view has focused primarily on the negative effects of stress on a variety of somatic systems, emerging data support the idea that certain forms of stress can enhance cellular function. Here we review the current literature on the hypothalamic-pituitary-adrenal (HPA) axis regulation by wheel running, a voluntary and controllable stressor with a distinct temporal profile. While running indeed activates a number of systems related to the stress response, other mechanisms exist to reduce the reactivity to this stressor, with possible crosstalk between running and other forms of stress.
TL;DR: Findings suggest that notch signaling in neurons, glia, and NSCs may be involved in pathological changes that occur in disorders such as stroke, Alzheimer’s disease and CNS tumors.
Abstract: Notch is an integral membrane protein that functions as receptor for ligands such as jagged and delta that are associated with the surface of neighboring cells. Upon ligand binding, notch is proteolytically cleaved within its transmembrane domain by presenilin-1 (the enzymatic component of the gamma-secretase complex) resulting in the release of a notch intracellular domain which translocates to the nucleus where it regulates gene expression. Notch signaling plays multiple roles in the development of the CNS including regulating neural stem cell (NSC) proliferation, survival, self-renewal and differentiation. Notch is also present in post-mitotic neurons in the adult CNS wherein its activation influences structural and functional plasticity including processes involved in learning and memory. Recent findings suggest that notch signaling in neurons, glia, and NSCs may be involved in pathological changes that occur in disorders such as stroke, Alzheimer's disease and CNS tumors. Studies of animal models suggest the potential of agents that target notch signaling as therapeutic interventions for several different CNS disorders.
TL;DR: A novel role for TLR3 is revealed in the negative regulation of NPC proliferation in the developing brain in wild type but notTLR3−/−-derived NPCs.
Abstract: Toll-like receptors (TLRs) play important roles in innate immunity. Several TLR family members have recently been shown to be expressed by neurons and glial cells in the adult brain, and may mediate responses of these cells to injury and infection. To address the possibility that TLRs play a functional role in development of the nervous system, we analyzed the expression of TLRs during different stages of mouse brain development and assessed the role of TLRs in cell proliferation. TLR3 protein is present in brain cells in early embryonic stages of development, and in cultured neural stem/progenitor cells (NPC). NPC from TLR3-deficient embryos formed greater numbers of neurospheres compared with neurospheres from wild-type embryos. Numbers of proliferating cells, as assessed by phospho histone H3 and proliferating cell nuclear antigen labeling, were also increased in the developing cortex of TLR3-deficient mice compared with wild-type mice in vivo. Treatment of cultured embryonic cortical neurospheres with a TLR3 ligand (polyIC) significantly reduced proliferating (BrdU-labeled) cells and neurosphere formation in wild type but not TLR3−/−-derived NPCs. Our findings reveal a novel role for TLR3 in the negative regulation of NPC proliferation in the developing brain.
TL;DR: By producing ATP and regulating intracellular calcium levels, mitochondria are vital for the function and survival of neurons and play important roles in aging and in the pathogenesis of neurodegenerative diseases.
TL;DR: It is reported that synaptosomes prepared from transgenic mice harboring presenilin‐1 mutations exhibit enhanced elevations of cytoplasmic calcium levels following exposure to depolarizing agents, amyloid β‐peptide, and a mitochondrial toxin compared with synaptoomes from nontransgenic mice and mice overexpressing wild‐type presenILin‐ 1.
Abstract: : Alzheimer's disease is characterized by amyloid β-peptide deposition, synapse loss, and neuronal death, which are correlated with cognitive impairments. Mutations in the presenilin-1 gene on chromosome 14 are causally linked to many cases of early-onset inherited Alzheimer's disease. We report that synaptosomes prepared from transgenic mice harboring presenilin-1 mutations exhibit enhanced elevations of cytoplasmic calcium levels following exposure to depolarizing agents, amyloid β-peptide, and a mitochondrial toxin compared with synaptosomes from nontransgenic mice and mice overexpressing wild-type presenilin-1. Mitochondrial dysfunction and caspase activation following exposures to amyloid β-peptide and metabolic insults were exacerbated in synaptosomes from presenilin-1 mutant mice. Agents that buffer cytoplasmic calcium or that prevent calcium release from the endoplasmic reticulum protected synaptosomes against the adverse effect of presenilin-1 mutations on mitochondrial function. Abnormal synaptic calcium homeostasis and mitochondrial dysfunction may contribute to the pathogenic mechanism of presenilin-1 mutations.
TL;DR: A role for CALM in directing VAMP2 trafficking during endocytosis is revealed, and the AP180 N‐terminal homology (ANTH) domain of CALM acts as a dominant‐negative mutant.
Abstract: Clathrin assembly lymphoid myeloid leukemia protein (CALM) is a clathrin assembly protein with a domain structure similar to the neuron-specific assembly protein AP180. We have previously found that CALM is expressed in neurons and present in synapses. We now report that CALM has a neuron-related function: it facilitates the endocytosis of the synaptic vesicle protein VAMP2 from the plasma membrane. Overexpression of CALM leads to the reduction of cell surface VAMP2, whereas knockdown of CALM by RNA interference results in the accumulation of surface VAMP2. The AP180 N-terminal homology (ANTH) domain of CALM is required for its effect on VAMP2 trafficking, and the ANTH domain itself acts as a dominant-negative mutant. Thus, our results reveal a role for CALM in directing VAMP2 trafficking during endocytosis.
TL;DR: The experimental findings in intact cardiac myocytes and neurons indicate that the current “dogma” related to the role of Ca2+ in MPT induction requires reevaluation, and emerging evidence suggests that after injury‐producing stresses, reactive oxygen species (but not Ca2+) are largely responsible for the pore induction.
Abstract: The mitochondrial permeability transition (MPT) pore complex is a key participant in the machinery that controls mitochondrial fate and, consequently, cell fate. The quest for the pore identity has been ongoing for several decades and yet the main structure remains unknown. Established "dogma" proposes that the core of the MPT pore is composed of an association of voltage-dependent anion channel (VDAC) and adenine nucleotide translocase (ANT). Recent genetic knockout experiments contradict this commonly accepted interpretation and provide a basis for substantial revision of the MPT pore identity. There is now sufficient evidence to exclude VDAC and ANT as the main pore structural components. Regarding MPT pore regulation, the role of cyclophilin D is confirmed and ANT may still serve some regulatory function, although the involvement of hexokinase II and creatine kinase remains unresolved. When cell protection signaling pathways are activated, we have found that the Bcl-2 family members relay the signal from glycogen synthase kinase-3 beta onto a target at or in close proximity to the pore. Our experimental findings in intact cardiac myocytes and neurons indicate that the current "dogma" related to the role of Ca2+ in MPT induction requires reevaluation. Emerging evidence suggests that after injury-producing stresses, reactive oxygen species (but not Ca2+) are largely responsible for the pore induction. In this article we discuss the current state of knowledge and provide new data related to the MPT pore structure and regulation.
TL;DR: Oxidative stress associated with iron deficiency anaemia in a murine model was studied feeding an iron-deficient diet and increased haemoglobin autoxidation and subsequent generation of ROS can account for the shorter RBC lifespan and other pathological changes associated withIron-deficiency anaemia.
Abstract: Oxidative stress associated with iron deficiency anaemia in a murine model was studied feeding an iron-deficient diet. Anaemia was monitored by a decrease in hematocrit and haemoglobin. For the 9 week study an increase in total iron binding capacity was also demonstrated. Anaemia resulted in an increase in red blood cells (RBC) oxidative stress as indicated by increased levels of fluorescent heme degradation products (1.24-fold after 5 weeks; 2.1-fold after 9 weeks). The increase in oxidative stress was further confirmed by elevated levels of methemoglobin for mice fed an iron-deficient diet. Increased haemoglobin autoxidation and subsequent generation of ROS can account for the shorter RBC lifespan and other pathological changes associated with iron-deficiency anaemia.
TL;DR: It is suggested that mild mitochondrial uncoupling and caloric restriction exert hormetic effects by stimulating bioenergetics in neurons thereby increasing tolerance of neurons to metabolic stress.
Abstract: Neurons are excitable cells that require large amounts of energy to support their survival and functions and are therefore prone to excitotoxicity, which involves energy depletion. By examining bioenergetic changes induced by glutamate, we found that the cellular nicotinamide adenine dinucleotide (NAD+) level is a critical determinant of neuronal survival. The bioenergetic effects of mitochondrial uncoupling and caloric restriction were also examined in cultured neurons and rodent brain. 2, 4-dinitrophenol (DNP) is a chemical mitochondrial uncoupler that stimulates glucose uptake and oxygen consumption on cultured neurons, which accelerates oxidation of NAD(P)H to NAD+ in mitochondria. The NAD+-dependent histone deacetylase sirtulin 1 (SIRT1) and glucose transporter 1 (GLUT1) mRNA are upregulated mouse brain under caloric restriction. To examine whether NAD+ mediates neuroprotective effects, nicotinamide, a precursor of NAD+ and inhibitor of SIRT1 and poly (ADP-ribose) polymerase 1 (PARP1) (two NAD+-dependent enzymes), was employed. Nicotinamide attenuated excitotoxic death and preserved cellular NAD+ levels to support SIRT1 and PARP 1 activities. Our findings suggest that mild mitochondrial uncoupling and caloric restriction exert hormetic effects by stimulating bioenergetics in neurons thereby increasing tolerance of neurons to metabolic stress.
TL;DR: The cellular and molecular mechanisms of hormesis are being revealed and include activation of growth factor signaling pathways, protein chaperones, cell survival genes and enzymes called sirtuins, leading to novel approaches for preventing and treating a range of human diseases.
Abstract: The survival of all organisms depends upon their ability to overcome stressful conditions, an ability that involves adaptive changes in cells and molecules. Findings from studies of animal models and human populations suggest that hormesis (beneficial effects of low levels of stress) is an effective means of protecting against many different diseases including diabetes, cardiovascular disease, cancers and neurodegenerative disorders. Such stress resistance mechanisms can be bolstered by diverse environmental factors including exercise, dietary restriction, cognitive stimulation and exposure to low levels of toxins. Some commonly used vitamins and dietary supplements may also induce beneficial stress responses. Several interrelated cellular signaling molecules are involved in the process of hormesis. Examples include the gases oxygen, carbon monoxide and nitric oxide, the neurotransmitter glutamate, the calcium ion and tumor necrosis factor. In each case low levels of these signaling molecules are beneficial and protect against disease, whereas high levels can cause the dysfunction and/or death of cells. The cellular and molecular mechanisms of hormesis are being revealed and include activation of growth factor signaling pathways, protein chaperones, cell survival genes and enzymes called sirtuins. Knowledge of hormesis mechanisms is leading to novel approaches for preventing and treating a range of human diseases.
TL;DR: The hypothesis that oxidized lipoproteins are one trigger for initiating early events in the pathogenesis of AMD is supported.
Abstract: The accumulation of apolipoprotein B100 lipoproteins in Bruch membrane is an early event thought to promote age-related macular degeneration (AMD). Immunohistochemistry using an anti-oxidized low density lipoprotein antibody on 10 AMD specimens showed staining in Bruch membrane including basal deposits, a marker of AMD. To determine whether retinal pigmented epithelial cells develop a pathologic phenotype after interaction with lipoproteins, ARPE-19 cells were exposed to low density lipoproteins (LDL) or oxidized LDLs (oxLDL). Analysis using the Affymetrix U133 Plus 2.0 (Affymetrix, Inc., Santa Clara, CA, USA) gene chip showed physiological and pathological transcriptional responses after LDL and oxLDL treatment, respectively. LDL induced a down-regulation of cholesterol biosynthesis genes while oxLDL induced transcriptional alterations in genes related to lipid metabolism, oxidative stress, inflammation and apoptosis. Electrospray mass spectrometry showed that oxLDL, but not LDL induced large cellular increases of sphingomyelin, ceramides, and cholesteryl esters. With TUNEL labeling, oxLDL caused 14.6% apoptosis compared to <1% after LDL. Addition of an inhibitor of sphingomyelin synthase inhibited this apoptosis by 41%. These data support the hypothesis that oxidized lipoproteins are one trigger for initiating early events in the pathogenesis of AMD.
TL;DR: A better understanding of how dietary energy intake affects reproductive axis function and endocrine pulsatility could provide novel strategies for the prevention and management of reproductive dysfunction and its associated comorbidities.
TL;DR: Different roles are suggested for the human Numb isoforms in APP metabolism and the expression of SPTB-Numb increases at the expense of LPTB-NUM in neuronal cultures subjected to stress, suggesting a role for Numb in stress-induced Aβ production.
TL;DR: A compendium of articles by Calabrese entitled “Neuroscience and Hormesis” provides a broad range of examples of neurobiological processes and responses to environmental factors that exhibit biphasic dose responses, the signature of hormesis.
Abstract: Hormesis is defined operationally as responses of cells or organisms to an exogenous or intrinsic factor (chemical, temperature, psychological challenge, etc.) in which the factor induces stimulatory or beneficial effects at low doses and inhibitory or adverse effects at high doses. The compendium of articles by Calabrese entitled “Neuroscience and Hormesis” provides a broad range of examples of neurobiological processes and responses to environmental factors that exhibit biphasic dose responses, the signature of hormesis. Nerve cell networks are the “first responders” to environmental challenges—they perceive the challenge and orchestrate coordinated adaptive responses that typically involve autonomic, neuroendocrine, and behavioral changes. In addition to direct adaptive responses of neurons to environmental stressors, cells subjected to a stressor produce and release molecules such as growth factors, cytokines, and hormones that alert adjacent and even distant cells to impending danger. The discoveries that some molecules (e.g., carbon monoxide and nitric oxide) and elements (e.g., selenium and iron) that are toxic at high doses play fundamental roles in cellular signaling or metabolism suggest that during evolution, organisms (and their nervous systems) co-opted environmental toxins and used them to their advantage. Neurons also respond adaptively to everyday stressors, including physical exercise, cognitive challenges, and dietary energy restriction, each of which activates pathways linked to the production of neurotrophic factors and cellular stress resistance proteins. The development of interventions that activate hormetic signaling pathways in neurons is a promising new approach for the preventation and treatment of a range of neurological disorders.
TL;DR: It is found that the glial progenitor proteoglycan NG2 is increased in parallel with GFAP during the symptomatic phase of the disease and that there is a differential in vitro response of SOD1G93A glia progenitors to inflammatory cytokines when compared to wildtype mouse glial PROGenitors.
Abstract: The focus of most neurodegenerative disease studies has been on neuronal death in particular subpopulations of the central nervous system. The associated response of glial populations has been ascribed the term "reactive astrocytosis." This has been defined as the proliferation of astrocytes accompanied by cellular hypertrophy and changes in gene expression following injury to the central nervous system. Yet the significance of that response to disease course is debated. In both human ALS and in the SOD1G93A mouse model of ALS, reactive astrocytosis is a hallmark of the disease--particularly at endstage. The brain also harbors immature progenitors which have the capacity for differentiation into both glial and neuronal lineages. We examined whether glial progenitors in the adult spinal cord of SOD1G93A mice become activated and contribute the astroglial response observed in this model. We found that the glial progenitor proteoglycan NG2 is increased in parallel with GFAP during the symptomatic phase of the disease and that there is a differential in vitro response of SOD1G93A glial progenitors to inflammatory cytokines when compared to wildtype mouse glial progenitors. This response was accompanied by the proliferation of glial progenitors but not mature GFAP+ astrocytes, through the translocation of the transcription factor Olig2 from the nucleus to the cytoplasm-resulting in astrocyte differentiation. These data suggest that adult glial progenitors from SOD1G93A mice differentially respond to inflammatory cytokines and contribute to the observed reactive astrocytosis observed in SOD1G93A mouse lumbar spinal cord.