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1.  Molecular changes in brain aging and Alzheimer’s disease are mirrored in experimentally silenced cortical neuron networks 
Neurobiology of aging  2010;33(1):205.e1-205.e18.
Activity-dependent modulation of neuronal gene expression promotes neuronal survival and plasticity, and neuronal network activity is perturbed in aging and Alzheimer’s disease (AD). Here we show that cerebral cortical neurons respond to chronic suppression of excitability by downregulating the expression of genes and their encoded proteins involved in inhibitory transmission (GABAergic and somatostatin) and Ca2+ signaling; alterations in pathways involved in lipid metabolism and energy management are also features of silenced neuronal networks. A molecular fingerprint strikingly similar to that of diminished network activity occurs in the human brain during aging and in AD, and opposite changes occur in response to activation of N-methyl-D-aspartate (NMDA) and brain-derived neurotrophic factor (BDNF) receptors in cultured cortical neurons and in mice in response to an enriched environment or electroconvulsive shock. Our findings suggest that reduced inhibitory neurotransmission during aging and in AD may be the result of compensatory responses that, paradoxically, render the neurons vulnerable to Ca2+-mediated degeneration.
doi:10.1016/j.neurobiolaging.2010.08.012
PMCID: PMC3027841  PMID: 20947216
Alzheimer’s disease; Aging; GABA; Activity; Homeostatic disinhibition; Interneuron; Calcium; Synaptic scaling
2.  Adiponectin protects rat hippocampal neurons against excitotoxicity 
Age  2010;33(2):155-165.
Adiponectin exerts multiple regulatory functions in the body and in the hypothalamus primarily through activation of its two receptors, adiponectin receptor1 and adiponectin receptor 2. Recent studies have shown that adiponectin receptors are widely expressed in other areas of the brain including the hippocampus. However, the functions of adiponectin in brain regions other than the hypothalamus are not clear. Here, we report that adiponectin can protect cultured hippocampal neurons against kainic acid-induced (KA) cytotoxicity. Adiponectin reduced the level of reactive oxygen species, attenuated apoptotic cell death, and also suppressed activation of caspase-3 induced by KA. Pretreatment of hippocampal primary neurons with an AMPK inhibitor, compound C, abolished adiponectin-induced neuronal protection. The AMPK activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, attenuated KA-induced caspase-3 activity. These findings suggest that the AMPK pathway is critically involved in adiponectin-induced neuroprotection and may mediate the antioxidative and anti-apoptotic properties of adiponectin.
doi:10.1007/s11357-010-9173-5
PMCID: PMC3127462  PMID: 20842535
Adiponectin; Neuroprotection; Hippocampus; Kainic acid; AMPK
3.  Neuronal Calcium Homeostasis and Dysregulation 
Antioxidants & Redox Signaling  2011;14(7):1261-1273.
Abstract
The calcium ion (Ca2+) is the main second messenger that helps to transmit depolarization status and synaptic activity to the biochemical machinery of a neuron. These features make Ca2+ regulation a critical process in neurons, which have developed extensive and intricate Ca2+ signaling pathways. High intensity Ca2+ signaling necessitates high ATP consumption to restore basal (low) intracellular Ca2+ levels after Ca2+ influx through plasma membrane receptor and voltage-dependent ion channels. Ca2+ influx may also lead to increased generation of mitochondrial reactive oxygen species (ROS). Impaired abilities of neurons to maintain cellular energy levels and to suppress ROS may impact Ca2+ signaling during aging and in neurodegenerative disease processes. This review focuses on mitochondrial and endoplasmic reticulum Ca2+ homeostasis and how they relate to synaptic Ca2+ signaling processes, neuronal energy metabolism, and ROS generation. Also, the contribution of altered Ca2+ signaling to neurodegeneration during aging will be considered. Advances in understanding the molecular regulation of Ca2+ homeostasis and how it is perturbed in neurological disorders may lead to therapeutic strategies that modulate neuronal Ca2+ signaling to enhance function and counteract disease processes. Antioxid. Redox Signal. 14, 1261–1273.
doi:10.1089/ars.2010.3386
PMCID: PMC3048837  PMID: 20626318
4.  An Overview of APP Processing Enzymes and Products 
Neuromolecular medicine  2010;12(1):1-12.
The generation of amyloid β-peptide (Aβ) by enzymatic cleavages of the β-amyloid precursor protein (APP) has been at the center of Alzheimer’s disease (AD) research. While the basic process of β- and γ-secretase-mediated generation of Aβ is text book knowledge, new aspects of Aβ and other cleavage products have emerged in recent years. Also our understanding of the enzymes involved in APP proteolysis has increased dramatically. All of these discoveries contribute to a more complete understanding of APP processing and the physiological and pathological roles of its secreted and intracellular protein products. Understanding APP processing is important for any therapeutic strategy aimed at reducing Aβ levels in AD. In this review we provide a concise description of the current state of understanding the enzymes involved in APP processing, the cleavage products generated by different processing patterns, and the potential functions of those cleavage products.
doi:10.1007/s12017-009-8104-z
PMCID: PMC2889200  PMID: 20232515
Amyloid beta; α-secretase; β-secretase; γ-secretase; APP; AICD
5.  hnRNP C promotes APP translation by competing with FMRP for APP mRNA recruitment to P bodies 
Amyloid precursor protein (APP) regulates neuronal synapse function and its cleavage product Aβ is linked to Alzheimer’s disease. Here, we present evidence that RNA-binding proteins (RBPs) heterogeneous nuclear ribonucleoprotein (hnRNP) C and fragile-X mental retardation protein (FMRP) associate with the same APP mRNA coding region element and influence APP translation competitively and in opposite directions. Silencing hnRNP C increased FMRP binding to APP mRNA and repressed APP translation, while silencing FMRP enhanced hnRNP C binding and promoted translation. Repression of APP translation was linked to colocalization of FMRP and tagged APP mRNA within processing bodies (PBs); this colocalization was abrogated by hnRNP C overexpression or FMRP silencing. Our findings indicate that FMRP represses translation by recruiting APP mRNA to PBs, while hnRNP C promotes APP translation by displacing FMRP, thereby relieving the translational block.
doi:10.1038/nsmb.1815
PMCID: PMC2908492  PMID: 20473314
6.  Alzheimer’s Disease and Neuronal Network Activity 
Neuromolecular medicine  2009;12(1):44-47.
doi:10.1007/s12017-009-8100-3
PMCID: PMC2833229  PMID: 19885650
Alzheimer’s Disease; Amyloid beta; GABA; Presenilin; neurofibrillary tangles; seizures; neuronal networks
7.  Simultaneous Single Neuron Recording of O2 Consumption, [Ca2+]i and Mitochondrial Membrane Potential in Glutamate Toxicity 
Journal of neurochemistry  2009;109(2):644-655.
To order the cellular processes in glutamate toxicity, we simultaneously recorded O2 consumption, cytosolic Ca2+ concentration ([Ca2+]i) and mitochondrial membrane potential (mΔψ) in single cortical neurons. O2 consumption was measured using an amperometric self-referencing platinum electrode adjacent to neurons in which [Ca2+]i and mΔψ were monitored with Fluo-4 and TMRE+, respectively using a spinning disk laser confocal microscope. Excitotoxic doses of glutamate caused an elevation of [Ca2+]i followed seconds afterwards by an increase in O2 consumption which reached a maximum level within 1 to 5 min. A modest increase in mΔψ occurred during this time period, and then, shortly before maximal O2 consumption was reached, the mΔψ, as indicated by TMRE+ fluorescence, dissipated. Maximal O2 consumption lasted up to 5 min and then declined together with mΔψ and ATP levels, while [Ca2+]i further increased. mΔψ and [Ca2+]i returned to baseline levels when neurons were treated with an N-methyl-D-aspartate receptor antagonist shortly after the [Ca2+]i increased. Our unprecedented spatial and time resolution revealed that this sequence of events is identical in all neurons, albeit with considerable variability in magnitude and kinetics of changes in O2 consumption, [Ca2+]i and mΔψ. The data obtained using this new method are consistent with a model where Ca2+ influx causes ATP depletion, despite maximal mitochondrial respiration, minutes after glutamate receptor activation.
doi:10.1111/j.1471-4159.2009.05997.x
PMCID: PMC2805059  PMID: 19226367
O2 consumption; glutamate; excitotoxicity
8.  Diminished iron concentrations increase adenosine A2A receptor levels in mouse striatum and cultured human neuroblastoma cells 
Experimental neurology  2008;215(2):236-242.
Brain iron insufficiency has been implicated in several neurological disorders. The dopamine system is consistently altered in studies of iron deficiency in rodent models. Changes in striatal dopamine D2 receptors are directly proportional to the degree of iron deficiency. In light of the unknown mechanism for the iron deficiency-dopamine connection and because of the known interplay between adenosinergic and dopaminergic systems in the striatum we examined the effects of iron deficiency on the adenosine system. We first attempted to assess whether there is a functional change in the levels of adenosine receptors in response to this low iron. Mice made iron-deficient by diet had an increase in the density of striatal adenosine A2A (A2AR) but not A1 receptor (A1R) compared to mice on a normal diet. Between two inbred murine strains, which had 2-fold differences in their striatal iron concentrations under normal dietary conditions, the strain with the lower striatal iron had the highest striatal A2AR density. Treatment of SH-SY5Y (human neuroblastoma) cells with an iron chelator resulted in increased density of A2AR. In these cells, A2AR agonist-induced cyclic AMP production was enhanced in response to iron chelation, also demonstrating a functional upregulation of A2AR. A significant correlation (r2=0.79) was found between a primary marker of cellular iron status (transferrin receptor (TfR)) and A2AR protein density. In conclusion, the A2AR is increased across different iron-insufficient conditions. The relation between A2AR and cellular iron status may be an important pathway by which adenosine may alter the function of the dopaminergic system.
doi:10.1016/j.expneurol.2008.10.007
PMCID: PMC2784599  PMID: 19013457
CGS-21680; Desferrioxamine; Dietary iron deficiency; Adenosine receptors; Restless legs syndrome; SH-SY5Y
9.  Mitochondria in Neuroplasticity and Neurological Disorders 
Neuron  2008;60(5):748-766.
Mitochondrial electron transport generates the ATP that is essential for the excitability and survival of neurons, and the protein phosphorylation reactions that mediate synaptic signaling and related long-term changes in neuronal structure and function. Mitochondria are highly dynamic organelles that divide, fuse and move purposefully within axons and dendrites. An Major functions of mitochondria in neurons include the regulation of Ca2+ and redox signaling, developmental and synaptic plasticity, and the arbitration of cell survival and death. The importance of mitochondria in neurons is evident in the neurological phenotypes in rare diseases caused by mutations in mitochondrial genes. Mitochondria-mediated oxidative stress, perturbed Ca2+ homeostasis and apoptosis may also contribute to the pathogenesis of prominent neurological diseases including Alzheimer’s, Parkinson’s and Huntington’s diseases, stroke, ALS and psychiatric disorders. Advances in understanding the molecular and cell biology of mitochondria are leading to novel approaches for the prevention and treatment of neurological disorders.
doi:10.1016/j.neuron.2008.10.010
PMCID: PMC2692277  PMID: 19081372
10.  Nicotinamide Prevents NAD+ Depletion and Protects Neurons Against Excitotoxicity and Cerebral Ischemia: NAD+ Consumption by SIRT1 may Endanger Energetically Compromised Neurons 
Neuromolecular medicine  2009;11(1):28-42.
Neurons require large amounts of energy to support their survival and function, and are therefore susceptible to excitotoxicity, a form of cell death involving bioenergetic stress that may occur in several neurological disorders including stroke and Alzheimer's disease. Here we studied the roles of NAD+ bioenergetic state, and the NAD+-dependent enzymes SIRT1 and PARP-1, in excitotoxic neuronal death in cultured neurons and in a mouse model of focal ischemic stroke. Excitotoxic activation of NMDA receptors induced a rapid decrease of cellular NAD(P)H levels and mitochondrial membrane potential. Decreased NAD+ levels and poly (ADP-ribose) polymer (PAR) accumulation in nuclei were relatively early events (<4 h) that preceded the appearance of propidium iodide-and TUNEL-positive cells (markers of necrotic cell death and DNA strand breakage, respectively) which became evident by 6 h. Nicotinamide, an NAD+ precursor and an inhibitor of SIRT1 and PARP1, inhibited SIRT1 deacetylase activity without affecting SIRT1 protein levels. NAD+ levels were preserved and PAR accumulation and neuronal death induced by excitotoxic insults were attenuated in nicotinamide-treated cells. Treatment of neurons with the SIRT1 activator resveratrol did not protect them from glutamate/NMDA-induced NAD+ depletion and death. In a mouse model of focal cerebral ischemic stroke, NAD+ levels were decreased in both the contralateral and ipsilateral cortex 6 h after the onset of ischemia. Stroke resulted in dynamic changes of SIRT1 protein and activity levels which varied among brain regions. Administration of nicotinamide (200 mg/kg, i.p.) up to 1 h after the onset of ischemia elevated brain NAD+ levels and reduced ischemic infarct size. Our findings demonstrate that the NAD+ bioenergetic state is critical in determining whether neurons live or die in excitotoxic and ischemic conditions, and suggest a potential therapeutic benefit in stroke of agents that preserve cellular NAD+ levels. Our data further suggest that, SIRT1 is linked to bioenergetic state and stress responses in neurons, and that under conditions of reduced cellular energy levels SIRT1 enzyme activity may consume sufficient NAD+ to nullify any cell survival-promoting effects of its deacetylase action on protein substrates.
doi:10.1007/s12017-009-8058-1
PMCID: PMC2677622  PMID: 19288225
Excitotoxicity; Glutamate; NMDA; NAD+; NADH; SIRT1; PARP-1; PAR; Nicotinamide; MCAO; TUNEL
11.  XRCC1 protects against the lethality of induced oxidative DNA damage in nondividing neural cells 
Nucleic Acids Research  2008;36(15):5111-5121.
XRCC1 is a critical scaffold protein that orchestrates efficient single-strand break repair (SSBR). Recent data has found an association of XRCC1 with proteins causally linked to human spinocerebellar ataxias—aprataxin and tyrosyl-DNA phosphodiesterase 1—implicating SSBR in protection against neuronal cell loss and neurodegenerative disease. We demonstrate herein that shRNA lentiviral-mediated XRCC1 knockdown in human SH-SY5Y neuroblastoma cells results in a largely selective increase in sensitivity of the nondividing (i.e. terminally differentiated) cell population to the redox-cycling agents, menadione and paraquat; this reduced survival was accompanied by an accumulation of DNA strand breaks. Using hypoxanthine–xanthine oxidase as the oxidizing method, XRCC1 deficiency affected both dividing and nondividing SH-SY5Y cells, with a greater effect on survival seen in the former case, suggesting that the spectrum of oxidative DNA damage created dictates the specific contribution of XRCC1 to cellular resistance. Primary XRCC1 heterozygous mouse cerebellar granule cells exhibit increased strand break accumulation and reduced survival due to increased apoptosis following menadione treatment. Moreover, knockdown of XRCC1 in primary human fetal brain neurons leads to enhanced sensitivity to menadione, as indicated by increased levels of DNA strand breaks relative to control cells. The cumulative results implicate XRCC1, and more broadly SSBR, in the protection of nondividing neuronal cells from the genotoxic consequences of oxidative stress.
doi:10.1093/nar/gkn480
PMCID: PMC2528184  PMID: 18682529

Results 1-11 (11)