Synaptic Deficits Are Rescued in the p25/Cdk5 Model of Neurodegeneration by the Reduction of β-Secretase (BACE1)

Alzheimer's disease (AD) is the most common cause of dementia, and is characterized by memory loss and cognitive decline, as well as amyloid β (Aβ) accumulation, and progressive neurodegeneration. Cdk5 is a proline-directed serine/threonine kinase whose activation by the p25 protein has been implicated in a number of neurodegenerative disorders. The CK-p25 inducible mouse model exhibits progressive neuronal death, elevated Aβ, reduced synaptic plasticity, and impaired learning following p25 overexpression in forebrain neurons. Levels of Aβ, as well as the APP processing enzyme, β-secretase (BACE1), are also increased in CK-p25 mice. It is unknown what role increased Aβ plays in the cognitive and neurodegenerative phenotype of the CK-p25 mouse. In the current work, we restored Aβ levels in the CK-p25 mouse to those of wild-type mice via the partial genetic deletion of BACE1, allowing us to examine the Aβ-independent phenotype of this mouse model. We show that, in the CK-p25 mouse, normalization of Aβ levels led to a rescue of synaptic and cognitive deficits. Conversely, neuronal loss was not ameliorated. Our findings indicate that increases in p25/Cdk5 activity may mediate cognitive and synaptic impairment via an Aβ-dependent pathway in the CK-p25 mouse. These findings explore the impact of targeting Aβ production in a mouse model of neurodegeneration and cognitive impairment, and how this may translate into therapeutic approaches for sporadic AD.National Institutes of Health (U.S.) (Grant NIH R01NS051874)Ruth L. Kirschstein National Research Service Award (Predoctoral Fellowship F31GM80055-03

A Dietary Regimen of Caloric Restriction or Pharmacological Activation of SIRT1 to Delay the Onset of Neurodegeneration

Caloric restriction (CR) is a dietary regimen known to promote lifespan by slowing down the occurrence of age-dependent diseases. The greatest risk factor for neurodegeneration in the brain is age, from which follows that CR might also attenuate the progressive loss of neurons that is often associated with impaired cognitive capacities. In this study, we used a transgenic mouse model that allows for a temporally and spatially controlled onset of neurodegeneration to test the potentially beneficial effects of CR. We found that in this model, CR significantly delayed the onset of neurodegeneration and synaptic loss and dysfunction, and thereby preserved cognitive capacities. Mechanistically, CR induced the expression of the known lifespan-regulating protein SIRT1, prompting us to test whether a pharmacological activation of SIRT1 might recapitulate CR. We found that oral administration of a SIRT1-activating compound essentially replicated the beneficial effects of CR. Thus, SIRT1-activating compounds might provide a pharmacological alternative to the regimen of CR against neurodegeneration and its associated ailments.National Institutes of Health (U.S.) (Grant PO1 AG027916

Diaminothiazoles Modify Tau Phosphorylation and Improve the Tauopathy in Mouse Models

Although Tau accumulation is a feature of several neurodegenerative conditions, treatment options for these conditions are nonexistent. Targeting Tau kinases represents a potential therapeutic approach. Small molecules in the diaminothiazole class are potent Tau kinase inhibitors that target CDK5 and GSK3?. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3? in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3×Tg-AD and CK-p25. Treatment nearly eliminated Sarkosyl-insoluble Tau with the most prominent effect on the phosphorylation at Ser-404. Treatment also induced the recovery of memory in a fear conditioning assay. Given the contribution of both CDK5/p25 and GSK3? to Tau phosphorylation, effective treatment of tauopathies may require dual kinase targeting

Basolateral amygdala bidirectionally modulates stress-induced hippocampal learning and memory deficits through a p25/Cdk5-dependent pathway

Repeated stress has been suggested to underlie learning and memory deficits via the basolateral amygdala (BLA) and the hippocampus; however, the functional contribution of BLA inputs to the hippocampus and their molecular repercussions are not well understood. Here we show that repeated stress is accompanied by generation of the Cdk5 (cyclin-dependent kinase 5)-activator p25, up-regulation and phosphorylation of glucocorticoid receptors, increased HDAC2 expression, and reduced expression of memory-related genes in the hippocampus. A combination of optogenetic and pharmacosynthetic approaches shows that BLA activation is both necessary and sufficient for stress-associated molecular changes and memory impairments. Furthermore, we show that this effect relies on direct glutamatergic projections from the BLA to the dorsal hippocampus. Finally, we show that p25 generation is necessary for the stress-induced memory dysfunction. Taken together, our data provide a neural circuit model for stress-induced hippocampal memory deficits through BLA activity-dependent p25 generation.National Institutes of Health (U.S.) (Grant AG047661)National Institutes of Health (U.S.) (Grant NS051874)JPB FoundationSwiss National Science Foundation (Grant for Prospective Researchers)Human Frontier Science Program (Strasbourg, France) (Long-Term Postdoctoral Fellowship

An epigenetic blockade of cognitive functions in the neurodegenerating brain

Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer’s disease [superscript 1]. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge [superscript 2]. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer’s-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer’s disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.Stanley Medical Research InstituteNational Institute of Neurological Disorders and Stroke (U.S.) (RO1NS078839)Swiss National Science FoundationBard Richmond (Fellowship)Simons FoundationTheodor und Ida Herzog-Egli Foundatio

An Epigenetic Blockade of Cognitive Functions in the Neurodegenerating Brain

Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer’s disease. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer’s-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer’s disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade

Le rôle de P53 en temps qu'inducteur de mort neuronale chez les souris p25

L association entre activation de p25/Cdk5 et un nombre varié de maladies neurodégénératives, l effet neuroprotecteur de l inhibition de la calpaine et/ou de l activité de cdk5 ainsi que la récapitulation des éléments clés du phénotype de type maladie d Alzheimer chez les souris surexprimant p25 sont des arguments très forts en faveur du rôle critique et crucial de p25/cdk5 comme inducteur de la mort neuronale dans ces maladies touchant le système nerveux central et particulièrement celle d Alzheimer. Ce processus est provoqué par l hyperphosphorylation de tau, la perte d intégrité du cytosquelette ainsi que celle de la mitochondrie, couplée à la production de radicaux libres et à la réentrée dans le cycle cellulaire.Dans cette étude nous avons utilisé le modèle de souris Ck-p25 pour étudier l implication de p53 dans ces événements et pour savoir si p53 est un élément primordial en aval de p25/cdk5 pour induire le stress cellulaire et la mort neuronale. Les résultats obtenus montrent que, suite à la surexpression de p25, l inhibition de p53 à la fois génétique et pharmacologique est capable de bloquer la réentrée dans le cycle cellulaire, la création de radicaux libres et la mort cellulaire, avec un effet bénéfique sur le comportement et les capacités de mémorisation de ces souris dans le test du fear conditioning . Pour nous permettre de publier ce travail et pour mieux comprendre le mécanisme de l induction de la mort neuronale par p25, nous chercherons à savoir quel est l effet de l activation de p53 par p25 sur HDAC1. En jouant sur l inhibition pharmacologique de p53 ou sa surexpression par transfection nous chercherons :1- quel est le mécanisme d action de p53 sur le niveau d expression et l activité de HDAC1, 2- si cet effet est impliqué dans le rôle de p53 comme activateur des dommages à l ADN et de la mort neuronale suite à l activation de p25. L utilisation d une forme mitochondriale de p53 devrait également nous dire si la fonction mitochondriale de p53 est importante pour induire ces effets délétères.Dans cette étude nous avons utilisé le modèle de souris Ck-p25 pour étudier l implication de p53 dans ces événements et pour savoir si p53 est un élément primordial en aval de p25/cdk5 pour induire le stress cellulaire et la mort neuronale. Les résultats obtenus montrent que, suite à la surexpression de p25, l inhibition de p53 à la fois génétique et pharmacologique est capable de bloquer la réentrée dans le cycle cellulaire, la création de radicaux libres et la mort cellulaire, avec un effet bénéfique sur le comportement et les capacités de mémorisation de ces souris dans le test du fear conditioning . Pour nous permettre de publier ce travail et pour mieux comprendre le mécanisme de l induction de la mort neuronale par p25, nous chercherons à savoir quel est l effet de l activation de p53 par p25 sur HDAC1. En jouant sur l inhibition pharmacologique de p53 ou sa surexpression par transfection nous chercherons :1- quel est le mécanisme d action de p53 sur le niveau d expression et l activité de HDAC1, 2- si cet effet est impliqué dans le rôle de p53 comme activateur des dommages à l ADN et de la mort neuronale suite à l activation de p25. L utilisation d une forme mitochondriale de p53 devrait également nous dire si la fonction mitochondriale de p53 est importante pour induire ces effets délétères.Dans cette étude nous avons utilisé le modèle de souris Ck-p25 pour étudier l implication de p53 dans ces événements et pour savoir si p53 est un élément primordial en aval de p25/cdk5 pour induire le stress cellulaire et la mort neuronale. Les résultats obtenus montrent que, suite à la surexpression de p25, l inhibition de p53 à la fois génétique et pharmacologique est capable de bloquer la réentrée dans le cycle cellulaire, la création de radicaux libres et la mort cellulaire, avec un effet bénéfique sur le comportement et les capacités de mémorisation de ces souris dans le test du fear conditioning . Pour nous permettre de publier ce travail et pour mieux comprendre le mécanisme de l induction de la mort neuronale par p25, nous chercherons à savoir quel est l effet de l activation de p53 par p25 sur HDAC1. En jouant sur l inhibition pharmacologique de p53 ou sa surexpression par transfection nous chercherons :1- quel est le mécanisme d action de p53 sur le niveau d expression et l activité de HDAC1, 2- si cet effet est impliqué dans le rôle de p53 comme activateur des dommages à l ADN et de la mort neuronale suite à l activation de p25. L utilisation d une forme mitochondriale de p53 devrait également nous dire si la fonction mitochondriale de p53 est importante pour induire ces effets délétères.Dans cette étude nous avons utilisé le modèle de souris Ck-p25 pour étudier l implication de p53 dans ces événements et pour savoir si p53 est un élément primordial en aval de p25/cdk5 pour induire le stress cellulaire et la mort neuronale. Les résultats obtenus montrent que, suite à la surexpression de p25, l inhibition de p53 à la fois génétique et pharmacologique est capable de bloquer la réentrée dans le cycle cellulaire, la création de radicaux libres et la mort cellulaire, avec un effet bénéfique sur le comportement et les capacités de mémorisation de ces souris dans le test du fear conditioning . Pour nous permettre de publier ce travail et pour mieux comprendre le mécanisme de l induction de la mort neuronale par p25, nous chercherons à savoir quel est l effet de l activation de p53 par p25 sur HDAC1. En jouant sur l inhibition pharmacologique de p53 ou sa surexpression par transfection nous chercherons : 1- quel est le mécanisme d action de p53 sur le niveau d expression et l activité de HDAC1, 2 - si cet effet est impliqué dans le rôle de p53 comme activateur des dommages à l ADN et de la mort neuronale suite à l activation de p25. L utilisation d une forme mitochondriale de p53 devrait également nous dire si la fonction mitochondriale de p53 est importante pour induire ces effets délétères.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Centrosome Motility Is Essential for Initial Axon Formation in the Neocortex

The mechanisms underlying the normal development of neuronal morphology remain a fundamental question in neurobiology. Studies in cultured neurons have suggested that the position of the centrosome and the Golgi may predict the site of axon outgrowth. During neuronal migration in the developing cortex, however, the centrosome and Golgi are oriented toward the cortical plate at a time when axons grow toward the ventricular zone. In the current work, we use in situ live imaging to demonstrate that the centrosome and the accompanying polarized cytoplasm exhibit apical translocation in newborn cortical neurons preceding initial axon outgrowth. Disruption of centrosomal activity or downregulation of the centriolar satellite protein PCM-1 affects axon formation. We further show that downregulation of the centrosomal protein Cep120 impairs microtubule organization, resulting in increased centrosome motility. Decreased centrosome motility resulting from microtubule stabilization causes an aberrant centrosomal localization, leading to misplaced axonal outgrowth. Our results reveal the dynamic nature of the centrosome in developing cortical neurons, and implicate centrosome translocation and microtubule organization during the multipolar stage as important determinants of axon formation.Simons Initiative on AutismThe Brain Infrastructure Grant ProgramKnut and Alice Wallenberg FoundationHoward Hughes Medical Institut

A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration

Caloric restriction (CR) is a dietary regimen known to promote lifespan by slowing down the occurrence of age-dependent diseases. The greatest risk factor for neurodegeneration in the brain is age, from which follows that CR might also attenuate the progressive loss of neurons that is often associated with impaired cognitive capacities. In this study, we used a transgenic mouse model that allows for a temporally and spatially controlled onset of neurodegeneration to test the potentially beneficial effects of CR. We found that in this model, CR significantly delayed the onset of neurodegeneration and synaptic loss and dysfunction, and thereby preserved cognitive capacities. Mechanistically, CR induced the expression of the known lifespan-regulating protein SIRT1, prompting us to test whether a pharmacological activation of SIRT1 might recapitulate CR. We found that oral administration of a SIRT1-activating compound essentially replicated the beneficial effects of CR. Thus, SIRT1-activating compounds might provide a pharmacological alternative to the regimen of CR against neurodegeneration and its associated ailments