- Email: [email protected]
45 Astrocyte-neuron metabolic coupling in Alzheimer's disease
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Abstracts / Neurobiology of Aging 33 (2012) S1–S38
ASTROCYTE-NEURON METABOLIC COUPLING IN ALZHEIMER’S DISEASE
Pierre Magistretti, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne EPFL, Lausanne, Switzerland. Contact e-mail: [email protected] One of the main features of AD is represented by alterations of the cerebral metabolic rate of glucose, the main energy substrate used by the brain (Zakzanis et al., 2003). A tight metabolic coupling between astrocytes and neurons is emerging as a key feature of brain energy metabolism (Belanger et al 2011, Allaman et al 2011). Over the years we have described two basic mechanisms of neurometabolic coupling. First the glycogenolytic effect of VIP - restricted to cortical columns - and of noradrenaline - spanning across functionally distinct cortical areas - indicating a regulation of brain homeostasis by neurotransmitters acting on astrocytes, as glycogen is exclusively localized in these cells (Magistretti, 2008). Second, the glutamate-stimulated aerobic glycolysis in astrocytes, mediated by the sodium-coupled reuptake of glutamate by astrocytes and the ensuing activation of the Na-K-ATPase, resulting in the release of lactate from astrocytes, which can then fuel the neuronal energy demands a mechanisms known as the ANLS (Pellerin and Magistretti 2011). Recently we have shown that the pathological form (1-42) of Abeta strongly affects the metabolic fates of glucose in astrocytes; it also increases hydrogen peroxide production and glutathione release, overall modifying the metabolic phenotype of astrocytes (Allaman et al, 2010). Aggregation and internalization into astrocytes through binding to class A scavenger receptors and activation of the PI3-kinase pathway mediate the effects of Abeta on glucose metabolism. Using astrocyte-neuron cocultures, we observed that the overall modifications of astrocyte metabolism induced by Abeta impair neuronal viability. These observations indicate that Abeta profoundly alters the metabolic phenotype of astrocytes with deleterious consequences for neuronal viability. We also recently showed that lactate derived from astrocytic glycogen is necessary for long-term memory consolidation and for induction of plasticity genes in neurons such as ARC and for maintenance of LTP (Suzuki et al, 2010). Overall these results indicate that astrocyte-neuron metabolic coupling in critical for cognitive functions and neuroprotection.
Changes of Tau in neurons (hyperphosphorylation, missorting, aggregation etc) are early signs of degeneration in Alzheimer disease. We are developing cell and animal models to study the progression of Tau pathology, the interaction with A-beta, and the effects of aggregation inhibitor compounds. Several cell and mouse models are based on the concept of regulatable expression of either “pro-aggregant” or “anti-aggregant” Tau which can be switched on or off by doxycyclin. The expressed Tau variants are derived from the FTDP17 mutation DeltaK280 which aggregates readily, whereas the anti-aggregant form contains two additional Ile⬎Pro mutations which prevent aggregation. In all models tested so far, pronounced signs of degeneration occur only when pro-aggregant Tau is expressed, whereas models with anti-aggregant Tau are nearly normal, indicating that the ability to aggregate is important for pathology. This correlates with the loss of synapses, followed by loss of neurons, and with learning and memory deficits. Importantly, the behavioral deficits can be rescued by switching off the expression of the toxic pro-aggregant tau. Synapse numbers return in spite of the persistence of mouse Tau aggregates and neuronal loss. This illustrates that Tau aggregates may have different degrees of toxicity. We are pursuing this concept on several levels: (a) regulatable transgenic mice (pro- or anti-aggregant, expressing repeat domain or fulllength Tau, (b) brain slices derived from the transgenic mice, (c) regulatable neuroblastoma cell models, (d) C. elegans models (collaboration E. Schmidt & R. Baumeister, Univ. Freiburg). In cell models, slice models, and C. elegans models the treatment with Tau aggregation inhibitors can rescue the deleterious effects of pro-aggregant forms of Tau, arguing that aggregation inhibitors might have the potential of slowing down the disease process in organisms as well. Moreover, differentiated neurons exposed to A-beta reveal that Tau missorting leads to the local loss of dendritic spines, local decay of microtubules, increase in Ca⫹⫹ and changes in Tau phosphorylation. Some of these disruptions of the cytoskeleton can be prevented by microtubule stabilizers. Overall, the data suggest that Tau pathology can be reversed, in principle, by reducing the level of aggregationcompetent Tau or by Tau aggregation inhibitors. Supported by MPG, EU FP7 (Memosad), Metlife Fnd, BMBF (KNDD), and Wellcome Trust.
47 46
REVERSIBILITY OF COGNITIVE DECLINE AND SYNAPSE LOSS IN REGULATABLE MICE WITH TAU PATHOLOGY
Eva-Maria Mandelkow, DZNE, German Center for Neurodegenerative Diseases, & CAESAR Research Center, Bonn, Germany. Contact e-mail: [email protected]
AFFITOPE®-BASED VACCINES: A NOVEL AND SAFE IMMUNOTHERAPEUTIC STRATEGY FOR NEURODEGENERATIVE DISEASES
Markus Mandler, A. Schneeberger, W. Schmidt, F. Mattner, AFFiRiS AG, Vienna, Austria. Contact e-mail: [email protected] Neurodegenerative diseases like AD and PD are character-
45
Abstracts / Neurobiology of Aging 33 (2012) S1–S38
ASTROCYTE-NEURON METABOLIC COUPLING IN ALZHEIMER’S DISEASE
Pierre Magistretti, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne EPFL, Lausanne, Switzerland. Contact e-mail: [email protected] One of the main features of AD is represented by alterations of the cerebral metabolic rate of glucose, the main energy substrate used by the brain (Zakzanis et al., 2003). A tight metabolic coupling between astrocytes and neurons is emerging as a key feature of brain energy metabolism (Belanger et al 2011, Allaman et al 2011). Over the years we have described two basic mechanisms of neurometabolic coupling. First the glycogenolytic effect of VIP - restricted to cortical columns - and of noradrenaline - spanning across functionally distinct cortical areas - indicating a regulation of brain homeostasis by neurotransmitters acting on astrocytes, as glycogen is exclusively localized in these cells (Magistretti, 2008). Second, the glutamate-stimulated aerobic glycolysis in astrocytes, mediated by the sodium-coupled reuptake of glutamate by astrocytes and the ensuing activation of the Na-K-ATPase, resulting in the release of lactate from astrocytes, which can then fuel the neuronal energy demands a mechanisms known as the ANLS (Pellerin and Magistretti 2011). Recently we have shown that the pathological form (1-42) of Abeta strongly affects the metabolic fates of glucose in astrocytes; it also increases hydrogen peroxide production and glutathione release, overall modifying the metabolic phenotype of astrocytes (Allaman et al, 2010). Aggregation and internalization into astrocytes through binding to class A scavenger receptors and activation of the PI3-kinase pathway mediate the effects of Abeta on glucose metabolism. Using astrocyte-neuron cocultures, we observed that the overall modifications of astrocyte metabolism induced by Abeta impair neuronal viability. These observations indicate that Abeta profoundly alters the metabolic phenotype of astrocytes with deleterious consequences for neuronal viability. We also recently showed that lactate derived from astrocytic glycogen is necessary for long-term memory consolidation and for induction of plasticity genes in neurons such as ARC and for maintenance of LTP (Suzuki et al, 2010). Overall these results indicate that astrocyte-neuron metabolic coupling in critical for cognitive functions and neuroprotection.
Changes of Tau in neurons (hyperphosphorylation, missorting, aggregation etc) are early signs of degeneration in Alzheimer disease. We are developing cell and animal models to study the progression of Tau pathology, the interaction with A-beta, and the effects of aggregation inhibitor compounds. Several cell and mouse models are based on the concept of regulatable expression of either “pro-aggregant” or “anti-aggregant” Tau which can be switched on or off by doxycyclin. The expressed Tau variants are derived from the FTDP17 mutation DeltaK280 which aggregates readily, whereas the anti-aggregant form contains two additional Ile⬎Pro mutations which prevent aggregation. In all models tested so far, pronounced signs of degeneration occur only when pro-aggregant Tau is expressed, whereas models with anti-aggregant Tau are nearly normal, indicating that the ability to aggregate is important for pathology. This correlates with the loss of synapses, followed by loss of neurons, and with learning and memory deficits. Importantly, the behavioral deficits can be rescued by switching off the expression of the toxic pro-aggregant tau. Synapse numbers return in spite of the persistence of mouse Tau aggregates and neuronal loss. This illustrates that Tau aggregates may have different degrees of toxicity. We are pursuing this concept on several levels: (a) regulatable transgenic mice (pro- or anti-aggregant, expressing repeat domain or fulllength Tau, (b) brain slices derived from the transgenic mice, (c) regulatable neuroblastoma cell models, (d) C. elegans models (collaboration E. Schmidt & R. Baumeister, Univ. Freiburg). In cell models, slice models, and C. elegans models the treatment with Tau aggregation inhibitors can rescue the deleterious effects of pro-aggregant forms of Tau, arguing that aggregation inhibitors might have the potential of slowing down the disease process in organisms as well. Moreover, differentiated neurons exposed to A-beta reveal that Tau missorting leads to the local loss of dendritic spines, local decay of microtubules, increase in Ca⫹⫹ and changes in Tau phosphorylation. Some of these disruptions of the cytoskeleton can be prevented by microtubule stabilizers. Overall, the data suggest that Tau pathology can be reversed, in principle, by reducing the level of aggregationcompetent Tau or by Tau aggregation inhibitors. Supported by MPG, EU FP7 (Memosad), Metlife Fnd, BMBF (KNDD), and Wellcome Trust.
47 46
REVERSIBILITY OF COGNITIVE DECLINE AND SYNAPSE LOSS IN REGULATABLE MICE WITH TAU PATHOLOGY
Eva-Maria Mandelkow, DZNE, German Center for Neurodegenerative Diseases, & CAESAR Research Center, Bonn, Germany. Contact e-mail: [email protected]
AFFITOPE®-BASED VACCINES: A NOVEL AND SAFE IMMUNOTHERAPEUTIC STRATEGY FOR NEURODEGENERATIVE DISEASES
Markus Mandler, A. Schneeberger, W. Schmidt, F. Mattner, AFFiRiS AG, Vienna, Austria. Contact e-mail: [email protected] Neurodegenerative diseases like AD and PD are character-