- Email: [email protected]
Profiling Of Membrane-anchored β-secretase Inhibitors In Cell Cultures
Poster Presentations P4-283
PLASMA NORADRENALINE LEVEL IN ALZHEIMER’S DISEASE AND MILD COGNITIVE IMPAIRMENT (MCI)
Mizuki Oka, Sakuragaoka Memorial Hospital, Tokyo, Japan. Contact e-mail: [email protected] Background: Noradrenaline (NA) is synthesized from dopamine by dopamine b-hydroxylase. It is released from the adrenal medulla, and is also a neurotransmitter in the central nervous system and sympathetic nervous system where it is released from noradrenergic neurons. NA released when a host of physiological changes are activated by a stressful event. In the brain, this is caused in part by activation of an area of the brain stem called the locus ceruleus (LC). This nucleus is the origin of norepinephrine pathways in the brain, including the hippocampus, entorhinal cortex, and frontal cortex. Physiologically, LC-derived NA plays an important role in selective attention, general arousal, and stress reactions to challenging environmental situations. Furthermore, NA has been implicated in a wide array of central processes and diseases, including learning and memory, neuronal excitability, drug addiction, pain, and affective disorders. And loss of LC neurons does contribute significantly to both in Alzheimer’s disease (AD) neuropathology and cognitive impairments. Although loss of noradrenergic neurons in the LC has been consistently demonstrated postmortem AD, several studies suggest that indices of central noradrenergic activity increase with the severity of AD in living patients. But the relationship between AD or mild cognitive impairment (MCI) and noradrenergic activity is not fully understood. Objective: To investigate the plasma NA level of AD and MCI. Methods: We chose 54 outpatients with clinical diagnosis of MCI (n¼22 mean MMSE:26.4, mean age:76.3) and probable AD (n¼32 mean MMSE:17.0, mean age:78.9) in the Memory Clinic, and check plasma NA concentration (normal values:100-450pg/ml) in the sitting position. Conclusion: Plasma NA level was significantly higher (p<0.01) in the patients with probable AD (mean value ¼ 891.1 pg/ml, SD ¼ 464.1) than in those with MCI (mean value ¼ 599.1 pg/ml, SD ¼ 154.1). Both plasma dopamine and adrenaline level were almost all normal level in the all patients. This results suggest that NA activity increase as the disease progress. Plasma NA levels may be a biomarker of the diagnosis of AD. And it might be a predictive factor of some BPSD that can contribute to nursing loads and the medical treatment economy. P4-284
CURRENT ANTICHOLINERGIC MEDICATION USE AND COGNITIVE IMPAIRMENT IN THE OLDER POPULATION: THE MEDICAL RESEARCH COUNCIL COGNITIVE FUNCTION AND AGEING STUDY
Kathryn Richardson1, Chris Fox2,3, Ian Maidment2,3, David Smithard4, Cornelius Katona2,5, Gill Livingston6,5, Malaz Boustani7, George M. Savva1, Simon Coulton3, Fiona E. Matthews8, Carol Brayne1, 1 University of Cambridge, Cambridge, United Kingdom; 2Kent and Medway NHS and Social Care Partnership Trust, West Malling, United Kingdom; 3 CHSS-University of Kent, Canterbury, United Kingdom; 4East Kent Hospitals University Trust, Ashford, United Kingdom; 5University College London, London, United Kingdom; 6Camden and Islington Mental Health and Social Care Trust, London, United Kingdom; 7Indiana University, Indianapolis, IN, USA; 8Medical Research Council Biostatistics Unit, Cambridge, United Kingdom. Contact e-mail: [email protected] Background: The cholinergic system has been implicated in cognitive impairment and is the target of Cholinesterase inhibitors, the primary pharmacotherapeutic treatment for Alzheimer’s disease. Cholinergic neurons degenerate with age hence the elderly are more susceptible to cognitive effects of anticholinergics. Objective: Anticholinergic medication use has been negatively associated with cognition in clinical settings and we sought to examine this in a population-based study. Methods: The anticholinergic burden scale which we have developed and validated previously was utilised to code medications reported at baseline in the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS). These were scored as 0 (none), 1 (mild), 2 (moderate), or 3 (severe) according to their anticho-
e13
linergic activity. Any discordance was resolved by discussion until a consensus was obtained. Scores were summed for each participant to give a total Anticholinergic Cognitive Burden (ACB) score. Incidence rate ratios for errors in the Mini-Mental State Examination (MMSE) associated with categories of ACB score (0, 1, 2, 3, 4 or 5þ) were calculated using negative binomial regression both unadjusted and adjusted for age, sex, education, social class, number of self-reported comorbidities, and number of other medications. Results: Of the 11,994 participants, 59% were female and the mean (SD) age was 75 (6.7) years. 26,759 prescription and over-the-counter medications were reported by 9,530 participants and 47% of participants reported taking medications with anticholinergic effects. A statistically significant dose-response relation was observed between increasing ACB score and decreasing MMSE, e.g. those with an ACB score of 5 or greater were associated with making 21% (95%CI 8%-35%) more errors on the MMSE than those not taking anticholinergics. However, the relationship with cognitive impairment was only seen for ACB conferred by Central Nervous System (CNS) medications, in particular antipsychotics. The ACB of non-CNS medications were not significantly associated with MMSE. Conclusion: Anticholinergic medication use in the older population was common. An inverse relation existed between the anticholinergic burden of current medication use and cognition, but the association was driven by the ACB of CNS medications. Longitudinal analyses in population-based studies are required to further examine the direction of causality. P4-285
PROFILING OF MEMBRANE-ANCHORED b-SECRETASE INHIBITORS IN CELL CULTURES
Heinke Schieb1, Hans-Joachim Kno¨lker2, Sebastian Weidlich2, Jens Wiltfang1, Hans W. Klafki1, 1Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, LVR-Klinikum Essen, Essen, Germany; 2Department of Chemistry, Technical University of Dresden, Dresden, Germany. Contact e-mail: [email protected] Background: Recently, Rajendran and coworkers demonstrated that the potency of a known b-secretase inhibitor can be substantially improved by targeting the compound to membranes by coupling it to a sterol moiety (Rajendran et al., Science 2008 Apr 25). The resulting ‘‘Tripartite Structure’’ - inhibitor is composed of three chemical modules, namely the pharmacophor, the lipid anchor responsible for membrane targeting, and a linker region to control the position of the pharmacophor relative to the lipid bilayer. Objective: To study how modifications of each of the three modules affect Aß generation in cell cultures. Methods: We have investigated the amount of Ab peptides secreted by primary chicken telencephalon cultures and by a neuroblastoma cell line (SY5Y) overexpressing APP wildtype (wt) and mutant APP (SWE), respectively. Results: Our findings indicate that the tripartite inhibitors carrying a peptide as pharmacophore potently reduce Abeta secretion from primary neuronal cells as well as from SH-SY5Y cells overexpressing wt and SWE APP. Importantly, BACE inhibition was observed at inhibitor concentrations that were at least 2 orders of magnitude below the concentrations that caused cell toxicity according to MTT and LDH ˚ and assays. The optimal linker length was determined to range from 35A ˚ . Replacing the cholesterol membrane anchor with oleyl or myristyl di89A minished the inhibition of Abeta secretion substantially. In contrast, a palmityl anchor resulted in only slighty reduced potency as compared to the cholesterol anchors. Conclusion: Taken together, these findings may help to optimize BACE inhibitor design and they may help to better understand the molecular details of APP processing and the generation of Abeta peptides and the involvement of cellular membranes. P4-286
STATIN USE IS NOT ASSOCIATED WITH COGNITIVE IMPAIRMENT IN A COHORT OF OLDER WOMEN
Eric B. Schneider, Michelle M. Mielke, Sevil Yasar, Michelle C. Carlson, Johns Hopkins University, Baltimore, MD, USA. Contact e-mail: eschneid@ jhsph.edu Background: Studies examining statin use and cognition in older adults have produced equivocal results. Objective: To determine whether statin use is
PLASMA NORADRENALINE LEVEL IN ALZHEIMER’S DISEASE AND MILD COGNITIVE IMPAIRMENT (MCI)
Mizuki Oka, Sakuragaoka Memorial Hospital, Tokyo, Japan. Contact e-mail: [email protected] Background: Noradrenaline (NA) is synthesized from dopamine by dopamine b-hydroxylase. It is released from the adrenal medulla, and is also a neurotransmitter in the central nervous system and sympathetic nervous system where it is released from noradrenergic neurons. NA released when a host of physiological changes are activated by a stressful event. In the brain, this is caused in part by activation of an area of the brain stem called the locus ceruleus (LC). This nucleus is the origin of norepinephrine pathways in the brain, including the hippocampus, entorhinal cortex, and frontal cortex. Physiologically, LC-derived NA plays an important role in selective attention, general arousal, and stress reactions to challenging environmental situations. Furthermore, NA has been implicated in a wide array of central processes and diseases, including learning and memory, neuronal excitability, drug addiction, pain, and affective disorders. And loss of LC neurons does contribute significantly to both in Alzheimer’s disease (AD) neuropathology and cognitive impairments. Although loss of noradrenergic neurons in the LC has been consistently demonstrated postmortem AD, several studies suggest that indices of central noradrenergic activity increase with the severity of AD in living patients. But the relationship between AD or mild cognitive impairment (MCI) and noradrenergic activity is not fully understood. Objective: To investigate the plasma NA level of AD and MCI. Methods: We chose 54 outpatients with clinical diagnosis of MCI (n¼22 mean MMSE:26.4, mean age:76.3) and probable AD (n¼32 mean MMSE:17.0, mean age:78.9) in the Memory Clinic, and check plasma NA concentration (normal values:100-450pg/ml) in the sitting position. Conclusion: Plasma NA level was significantly higher (p<0.01) in the patients with probable AD (mean value ¼ 891.1 pg/ml, SD ¼ 464.1) than in those with MCI (mean value ¼ 599.1 pg/ml, SD ¼ 154.1). Both plasma dopamine and adrenaline level were almost all normal level in the all patients. This results suggest that NA activity increase as the disease progress. Plasma NA levels may be a biomarker of the diagnosis of AD. And it might be a predictive factor of some BPSD that can contribute to nursing loads and the medical treatment economy. P4-284
CURRENT ANTICHOLINERGIC MEDICATION USE AND COGNITIVE IMPAIRMENT IN THE OLDER POPULATION: THE MEDICAL RESEARCH COUNCIL COGNITIVE FUNCTION AND AGEING STUDY
Kathryn Richardson1, Chris Fox2,3, Ian Maidment2,3, David Smithard4, Cornelius Katona2,5, Gill Livingston6,5, Malaz Boustani7, George M. Savva1, Simon Coulton3, Fiona E. Matthews8, Carol Brayne1, 1 University of Cambridge, Cambridge, United Kingdom; 2Kent and Medway NHS and Social Care Partnership Trust, West Malling, United Kingdom; 3 CHSS-University of Kent, Canterbury, United Kingdom; 4East Kent Hospitals University Trust, Ashford, United Kingdom; 5University College London, London, United Kingdom; 6Camden and Islington Mental Health and Social Care Trust, London, United Kingdom; 7Indiana University, Indianapolis, IN, USA; 8Medical Research Council Biostatistics Unit, Cambridge, United Kingdom. Contact e-mail: [email protected] Background: The cholinergic system has been implicated in cognitive impairment and is the target of Cholinesterase inhibitors, the primary pharmacotherapeutic treatment for Alzheimer’s disease. Cholinergic neurons degenerate with age hence the elderly are more susceptible to cognitive effects of anticholinergics. Objective: Anticholinergic medication use has been negatively associated with cognition in clinical settings and we sought to examine this in a population-based study. Methods: The anticholinergic burden scale which we have developed and validated previously was utilised to code medications reported at baseline in the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS). These were scored as 0 (none), 1 (mild), 2 (moderate), or 3 (severe) according to their anticho-
e13
linergic activity. Any discordance was resolved by discussion until a consensus was obtained. Scores were summed for each participant to give a total Anticholinergic Cognitive Burden (ACB) score. Incidence rate ratios for errors in the Mini-Mental State Examination (MMSE) associated with categories of ACB score (0, 1, 2, 3, 4 or 5þ) were calculated using negative binomial regression both unadjusted and adjusted for age, sex, education, social class, number of self-reported comorbidities, and number of other medications. Results: Of the 11,994 participants, 59% were female and the mean (SD) age was 75 (6.7) years. 26,759 prescription and over-the-counter medications were reported by 9,530 participants and 47% of participants reported taking medications with anticholinergic effects. A statistically significant dose-response relation was observed between increasing ACB score and decreasing MMSE, e.g. those with an ACB score of 5 or greater were associated with making 21% (95%CI 8%-35%) more errors on the MMSE than those not taking anticholinergics. However, the relationship with cognitive impairment was only seen for ACB conferred by Central Nervous System (CNS) medications, in particular antipsychotics. The ACB of non-CNS medications were not significantly associated with MMSE. Conclusion: Anticholinergic medication use in the older population was common. An inverse relation existed between the anticholinergic burden of current medication use and cognition, but the association was driven by the ACB of CNS medications. Longitudinal analyses in population-based studies are required to further examine the direction of causality. P4-285
PROFILING OF MEMBRANE-ANCHORED b-SECRETASE INHIBITORS IN CELL CULTURES
Heinke Schieb1, Hans-Joachim Kno¨lker2, Sebastian Weidlich2, Jens Wiltfang1, Hans W. Klafki1, 1Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, LVR-Klinikum Essen, Essen, Germany; 2Department of Chemistry, Technical University of Dresden, Dresden, Germany. Contact e-mail: [email protected] Background: Recently, Rajendran and coworkers demonstrated that the potency of a known b-secretase inhibitor can be substantially improved by targeting the compound to membranes by coupling it to a sterol moiety (Rajendran et al., Science 2008 Apr 25). The resulting ‘‘Tripartite Structure’’ - inhibitor is composed of three chemical modules, namely the pharmacophor, the lipid anchor responsible for membrane targeting, and a linker region to control the position of the pharmacophor relative to the lipid bilayer. Objective: To study how modifications of each of the three modules affect Aß generation in cell cultures. Methods: We have investigated the amount of Ab peptides secreted by primary chicken telencephalon cultures and by a neuroblastoma cell line (SY5Y) overexpressing APP wildtype (wt) and mutant APP (SWE), respectively. Results: Our findings indicate that the tripartite inhibitors carrying a peptide as pharmacophore potently reduce Abeta secretion from primary neuronal cells as well as from SH-SY5Y cells overexpressing wt and SWE APP. Importantly, BACE inhibition was observed at inhibitor concentrations that were at least 2 orders of magnitude below the concentrations that caused cell toxicity according to MTT and LDH ˚ and assays. The optimal linker length was determined to range from 35A ˚ . Replacing the cholesterol membrane anchor with oleyl or myristyl di89A minished the inhibition of Abeta secretion substantially. In contrast, a palmityl anchor resulted in only slighty reduced potency as compared to the cholesterol anchors. Conclusion: Taken together, these findings may help to optimize BACE inhibitor design and they may help to better understand the molecular details of APP processing and the generation of Abeta peptides and the involvement of cellular membranes. P4-286
STATIN USE IS NOT ASSOCIATED WITH COGNITIVE IMPAIRMENT IN A COHORT OF OLDER WOMEN
Eric B. Schneider, Michelle M. Mielke, Sevil Yasar, Michelle C. Carlson, Johns Hopkins University, Baltimore, MD, USA. Contact e-mail: eschneid@ jhsph.edu Background: Studies examining statin use and cognition in older adults have produced equivocal results. Objective: To determine whether statin use is