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PL.02.01 CSF biomarkers in Alzheimer's disease – use in clinical diagnosis and to monitor treatment effects
S159
Plenary lectures
PL.02. ECNP Neuropsychopharmacology Award lecture PL.02.01 CSF biomarkers in Alzheimer’s disease − use in clinical diagnosis and to monitor treatment effects K. Blennow1 ° . 1 G¨oteborg University, Sahlgren’s University HospitalClinical Neurochemistry Lab, M¨olndal, Sweden Research advances on the molecular pathogenesis of AD have been translated into novel drug candidates, such as b-amyloid (Ab) immunotherapy and secretase inhibitors, with disease-modifying potential. If these drugs prove to be effective, CSF biomarkers for AD will be important tools for early diagnosis, to enable early initiation of treatment. Specific immunoassays have been developed and validated for different isoforms of the central proteins involved in AD pathogenesis, tau and Ab. These CSF biomarkers have been shown to have a high diagnostic accuracy for AD, and recent multi-centre studies also show that CSF biomarkers can identify prodromal AD in patients with mild cognitive impairment. CSF biomarkers may be valuable tools to identify and monitor the biochemical effect of Ab modulatory drug candidates directly in AD patients. CSF analyses enables monitoring several aspects of APP/Ab metabolism, including Ab isoforms, APP isoforms (bsAPP and a-sAPP), Ab oligomers, and secretase (BACE1) activity. Using targeted proteomics techniques, novel shorter Ab isoforms (Ab15 and Ab16) have been identified that show promise as tools to monitor g-secretase inhibitor therapy. Last, CSF biomarkers may also be useful to study the molecular pathogenesis of AD directly in living patients. Using this approach, a novel pathway for APP processing and Ab production, involving the concerted action of b-secretase and g-secretase, was recently identified. Taken together, these data suggest that CSF biomarkers have the potential both to serve as diagnostic and theragnostic biochemical markers for AD, and as tools to verify pathogenic events directly in patients with the disease.
PL.03. Plenary lecture PL.03.01 Epigenetic regulation of cognitive functions I. Mansuy1 ° , K. Koshibu2 , J. Graeff2 . 1 Brain Research Institute, Epigenetic dysregulations in psychiatric diseases, Z¨urich, Switzerland; 2 Brain Research Institute, University/ETH Z¨urich, Z¨urich, Switzerland Cognitive functions have complex modes of regulation known to recruit multiple mechanisms but which remain not fully understood. Epigenetic mechanisms, in particular chromatin remodeling, have recently been recognized to be critical for such regulation. These mechanisms are complex and involve posttranslational modifications of histone proteins, DNA methylation, RNA interference and/or nucleosome positioning, and an interplay between
these processes. Their ultimate effect is to induce changes in gene expression in individual cells or structures, which can be dynamic and transient, or more permanent. In the adult brain, these changes are important for cognitive processes such as learning and memory formation. Their alteration in the diseased or aged brain is thought to contribute to the etiology of memory disorders, cognitive decline and neurodegenerative diseases like Alzheimer’s disease. This talk will present experimental evidence showing that the epigenetic regulation of learning and memory in the adult brain depends on the protein phosphatase PP1. It will demonstrate that PP1 is present at the chromatin and interacts with important enzymes of the epigenetic machinery including HDAC1 (histone deacetylase 1) and histone demethylase JMJD2A (jumonji domain-containing protein 2A). The selective inhibition of PP1 in the nucleus of forebrain neurons induces several histone PTMs, which are residue-specific and occur at the promoter of genes important for memory formation. These histone PTMs are also associated with improved long-term memory for objects and space. Overall, these findings reveal a novel mechanism for the epigenetic control of gene transcription and long-term memory that depends on PP1 [1]. References [1] Koshibu, K., Graeff, J, Beullens, M., Heitz, F., Berchtold, D., Russig, H., Farinelli, M, Bollen, M and Mansuy I.M. (2009). Protein phosphatase 1 regulates the histone code for long-term memory formation. J. Neurosci. 29, 13079−89.
Plenary lectures
PL.02. ECNP Neuropsychopharmacology Award lecture PL.02.01 CSF biomarkers in Alzheimer’s disease − use in clinical diagnosis and to monitor treatment effects K. Blennow1 ° . 1 G¨oteborg University, Sahlgren’s University HospitalClinical Neurochemistry Lab, M¨olndal, Sweden Research advances on the molecular pathogenesis of AD have been translated into novel drug candidates, such as b-amyloid (Ab) immunotherapy and secretase inhibitors, with disease-modifying potential. If these drugs prove to be effective, CSF biomarkers for AD will be important tools for early diagnosis, to enable early initiation of treatment. Specific immunoassays have been developed and validated for different isoforms of the central proteins involved in AD pathogenesis, tau and Ab. These CSF biomarkers have been shown to have a high diagnostic accuracy for AD, and recent multi-centre studies also show that CSF biomarkers can identify prodromal AD in patients with mild cognitive impairment. CSF biomarkers may be valuable tools to identify and monitor the biochemical effect of Ab modulatory drug candidates directly in AD patients. CSF analyses enables monitoring several aspects of APP/Ab metabolism, including Ab isoforms, APP isoforms (bsAPP and a-sAPP), Ab oligomers, and secretase (BACE1) activity. Using targeted proteomics techniques, novel shorter Ab isoforms (Ab15 and Ab16) have been identified that show promise as tools to monitor g-secretase inhibitor therapy. Last, CSF biomarkers may also be useful to study the molecular pathogenesis of AD directly in living patients. Using this approach, a novel pathway for APP processing and Ab production, involving the concerted action of b-secretase and g-secretase, was recently identified. Taken together, these data suggest that CSF biomarkers have the potential both to serve as diagnostic and theragnostic biochemical markers for AD, and as tools to verify pathogenic events directly in patients with the disease.
PL.03. Plenary lecture PL.03.01 Epigenetic regulation of cognitive functions I. Mansuy1 ° , K. Koshibu2 , J. Graeff2 . 1 Brain Research Institute, Epigenetic dysregulations in psychiatric diseases, Z¨urich, Switzerland; 2 Brain Research Institute, University/ETH Z¨urich, Z¨urich, Switzerland Cognitive functions have complex modes of regulation known to recruit multiple mechanisms but which remain not fully understood. Epigenetic mechanisms, in particular chromatin remodeling, have recently been recognized to be critical for such regulation. These mechanisms are complex and involve posttranslational modifications of histone proteins, DNA methylation, RNA interference and/or nucleosome positioning, and an interplay between
these processes. Their ultimate effect is to induce changes in gene expression in individual cells or structures, which can be dynamic and transient, or more permanent. In the adult brain, these changes are important for cognitive processes such as learning and memory formation. Their alteration in the diseased or aged brain is thought to contribute to the etiology of memory disorders, cognitive decline and neurodegenerative diseases like Alzheimer’s disease. This talk will present experimental evidence showing that the epigenetic regulation of learning and memory in the adult brain depends on the protein phosphatase PP1. It will demonstrate that PP1 is present at the chromatin and interacts with important enzymes of the epigenetic machinery including HDAC1 (histone deacetylase 1) and histone demethylase JMJD2A (jumonji domain-containing protein 2A). The selective inhibition of PP1 in the nucleus of forebrain neurons induces several histone PTMs, which are residue-specific and occur at the promoter of genes important for memory formation. These histone PTMs are also associated with improved long-term memory for objects and space. Overall, these findings reveal a novel mechanism for the epigenetic control of gene transcription and long-term memory that depends on PP1 [1]. References [1] Koshibu, K., Graeff, J, Beullens, M., Heitz, F., Berchtold, D., Russig, H., Farinelli, M, Bollen, M and Mansuy I.M. (2009). Protein phosphatase 1 regulates the histone code for long-term memory formation. J. Neurosci. 29, 13079−89.