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342 Prolyl endopeptidase inhibitor, JTP-4819, for Alzheimer's disease
$86
FIFTH INTERNATIONAL CONFERENCE ON ALZHEIMER'S DISEASE
We found a novel gene encoding a serine protease termed
ROUNDTABLE M: ALZHEIMER'S DISEASE: MAGNITUDE AND MEDICAL OPPORTUNITIES
neuropsin. In situ hybridization analyses demonstrated that neuropsin mRNA is expressed specifically in the hippocampal CA1-3 subfields, the amygdaloid complex, the lateral and medial septal nuclei, the diagonal band, the frontal cerebral cortex, and the anterior olfactory nucleus. The ontogeny of neuropsin mRNA expression was also analysed by in situ hybridization histochemistry, in the 18 days embryo, primordal pyramidal cells of the lateral part of the CA3 subfield were first labeled by the neuropsin probe. From this stage, weak hybridization signals were also found into the Iimbic/neocortical areas via cingulate/retorsprenial cortices. Signals increased in number in the CA3 subfield between 18 days embryo and postnatal day 5. After postnatal day 5, the hybridization signals increased sharply and extended from CA3 to CA1. The signals then maintained their intensity in adult. Direct hippocampal stimulation, kindling induced by amygdaloid stimulation, and hippocampal long-term potentiation caused a significant bilateral change in neuropsin mRNA level in the hippocampal pyramidal neurons. The activity-dependent changes and the specific localization indicate that neuropsin is involved in hippocampal plasticity.
343 Changing Trend of Prevalence Pattern of Age-associated Dementia: What Recent Epidemiology on Dementia Teaches us K. Hasegawa* St. Marianna University School of Medicine, Kawasaki, Japan Epidemiology teaches us the pattern of the illness subjected to the study. Firstly epidemiological studies are an essential part of the investigation of diseases with unknown etiology and secondly epidemiology provides basic data for establishing a medico-social strategy against the disease. We have recently observed a changing pattern of age-associated dementia from which we have learned valuable lessons. Since 1974, when the first large scale prevalence study on age-associated dementia was carried out by the author in Tokyo, about 30 local governments throughout Japan have administered similar population surveys in those aged 65 years old and over. The findings have been consistent. The prevalences of vascular dementia Were consistently higher than those of Alzheimer's disease in most of Japanese surveys, which is the converse of the results of Western surveys. However, recently several studies have shown a changing pattern, Alzheimer's disease being seen more frequently than vascular dementia, and some studies have indicated a decrease in the prevalence rate of the age-associated dementia, despite an increasingly aging population. The author will discuss possible hypotheses to explain this new trend.
342
Prolyl Endopeptidase Inhibitor, JTP-4819, for Alzheimer's Disease K. Toide*, M, Shinoda; Y. lwamoto, and T. Fujiwara Central Pharmaceutical Research Institute, Japan Tobacco Inc.,l-I Murasaki-cho, Takatsuki, Osaka 569, Japan Some neuropeptide-containing neuron populations are abnormal in Alzheimer's disease, suggesting that enhancement of peptidergic neurotransmission by inhibiting certain peptidases may have therapeutic value. Prolyl endopeptidase (PEP) may play a role in the metabolism of proline-containing neuropeptides such as substance P (SP), arginine-vasopressin (AVP), and TRH. There is evidence that these neuropeptides can enhance learning and memory, and have neurotrophic or neuroprotective effects. With the aim of treating for Alzheimer's disease, we developed a novel PEP inhibitor, (S)-2-[[(S)-2-(hydroxyacetyl)-lpyrrolidinyl]carbonyl]-N-(phenylmethyl)- I -pyrrolidinecarboxamide (JTP-4819). JTP-4819 strongly and specifically inhibited PEP activity in the rat brain (IC5o = 0.83 riM). Ex vivo enzyme activity studies showed that JTP-4819 (3 mg/kg, p.o,) inhibited PEP activity in the cerebral cortex, hippocampus, corpus striatum, and other brain regions of rats. JTP-4819 inhibited degradation of SP, AVP, and TRH by PEP in rat cortical and hippocampal supernatants with 1C5ovalues of the nanomolar order. Cortical and/or hippocampal SP-like immunoreactivity (SP-LI) and TRH-LI significantly decreased in aged rats. Administration of JTP-aRI9 (0.3 and/or 1 mg/kg, p.o.) for 21 days significantly reversed this decrease of SP-LI and TRH-LI. A study employing the Morris water maze task demonstrated that repeated administration of JTP-4819 (1.0 and/or 3 mg/kg, p.o.) ameliorated memory deficits in aged rats, rats with middle cerebral artery occlusion, and rats with nucleus basalis magnocellularis lesions. JTP-4819 (1-10 mg/kg, p.o.) also significantly prolonged the retention time in scopolamine-treated rats performing the passive avoidance task. Coadministration of JTP-4819 with S P, AVP, or TRH (at doses where each agent alone did not prolong retention) increased the retention time in scopolamine-treated rats, suggestingthe activation of peptidergic neurons. A microdialysis study demonstrated that JTP-4819 (3 mg/kg, p.o.) significantly increased ACh release in the frontal cortex and hippocampus of aged rats, suggesting the activation of cholinergic neurons. Recently, we found that JTP4819 inhibited 6-amyloid production by NGI08-15 cells, indicating that it might also slow the progression of Alzheimer's disease. Taken together, these pharmacological actions of .1TP-4819 suggest that it may be of therapeutic value for Alzheimer's disease.
344
Incidence of Alzhehner's Disease: The E U R O D E M Experience L.J. Lanner*, L.A. Amaducci, K. Andersen, J.F. Dartigues, P. Kragh-Sorensen, L. Letenneur, A. Lobo, J.M. Martinez-Lage, the MRC CFAS Study Group, A. Ott, A. HofnJan for the Eurodem Incidence Research Group There are few population-based studies of the incidence of dementing diseases. In particular incidence data on the most common form of dementing disease, Alzheimer's disease are lacking. Y e t such data are needed to identify risk factors for disease onset. EURODEM is a European Union funded network of centres involved in implementing population-based studies on epidemiology of dementing diseases, including Alzheimer's disease. The objectives of EURODEM are to (1) examine geographic variation in incidence rates of dementing diseases; (2) examine risk factors for incident dementing diseases. EURODEM studies include community-dwelling and institutionalized individuals aged 65 years and older. A two stage procedure is used to identify cases. This includes screening the total population on cognitive function, and performing a more detailed clinical assessment on screen positive respondents. Cases are reviewed by a EURODEM case review board, for consistency in diagnosis across the various centres. Data on a core set of risk factors collected by all studies. Currently, 570 cases have been identified including over 36,000 person-years in the context of five of the EURODEM studies. These studies are located in France (PAQUID Study), Denmark (Odense Study), the Netherlands (Rotterdam Study), and the United Kingdom (Medical Research Council Cognitive Function and Aging Study including the Liverpool MRC-Alpha Study). In this presentation we will give the age and sex stratified incident rates for all dementia and by sub-type for individual studies and for the total group.
FIFTH INTERNATIONAL CONFERENCE ON ALZHEIMER'S DISEASE
We found a novel gene encoding a serine protease termed
ROUNDTABLE M: ALZHEIMER'S DISEASE: MAGNITUDE AND MEDICAL OPPORTUNITIES
neuropsin. In situ hybridization analyses demonstrated that neuropsin mRNA is expressed specifically in the hippocampal CA1-3 subfields, the amygdaloid complex, the lateral and medial septal nuclei, the diagonal band, the frontal cerebral cortex, and the anterior olfactory nucleus. The ontogeny of neuropsin mRNA expression was also analysed by in situ hybridization histochemistry, in the 18 days embryo, primordal pyramidal cells of the lateral part of the CA3 subfield were first labeled by the neuropsin probe. From this stage, weak hybridization signals were also found into the Iimbic/neocortical areas via cingulate/retorsprenial cortices. Signals increased in number in the CA3 subfield between 18 days embryo and postnatal day 5. After postnatal day 5, the hybridization signals increased sharply and extended from CA3 to CA1. The signals then maintained their intensity in adult. Direct hippocampal stimulation, kindling induced by amygdaloid stimulation, and hippocampal long-term potentiation caused a significant bilateral change in neuropsin mRNA level in the hippocampal pyramidal neurons. The activity-dependent changes and the specific localization indicate that neuropsin is involved in hippocampal plasticity.
343 Changing Trend of Prevalence Pattern of Age-associated Dementia: What Recent Epidemiology on Dementia Teaches us K. Hasegawa* St. Marianna University School of Medicine, Kawasaki, Japan Epidemiology teaches us the pattern of the illness subjected to the study. Firstly epidemiological studies are an essential part of the investigation of diseases with unknown etiology and secondly epidemiology provides basic data for establishing a medico-social strategy against the disease. We have recently observed a changing pattern of age-associated dementia from which we have learned valuable lessons. Since 1974, when the first large scale prevalence study on age-associated dementia was carried out by the author in Tokyo, about 30 local governments throughout Japan have administered similar population surveys in those aged 65 years old and over. The findings have been consistent. The prevalences of vascular dementia Were consistently higher than those of Alzheimer's disease in most of Japanese surveys, which is the converse of the results of Western surveys. However, recently several studies have shown a changing pattern, Alzheimer's disease being seen more frequently than vascular dementia, and some studies have indicated a decrease in the prevalence rate of the age-associated dementia, despite an increasingly aging population. The author will discuss possible hypotheses to explain this new trend.
342
Prolyl Endopeptidase Inhibitor, JTP-4819, for Alzheimer's Disease K. Toide*, M, Shinoda; Y. lwamoto, and T. Fujiwara Central Pharmaceutical Research Institute, Japan Tobacco Inc.,l-I Murasaki-cho, Takatsuki, Osaka 569, Japan Some neuropeptide-containing neuron populations are abnormal in Alzheimer's disease, suggesting that enhancement of peptidergic neurotransmission by inhibiting certain peptidases may have therapeutic value. Prolyl endopeptidase (PEP) may play a role in the metabolism of proline-containing neuropeptides such as substance P (SP), arginine-vasopressin (AVP), and TRH. There is evidence that these neuropeptides can enhance learning and memory, and have neurotrophic or neuroprotective effects. With the aim of treating for Alzheimer's disease, we developed a novel PEP inhibitor, (S)-2-[[(S)-2-(hydroxyacetyl)-lpyrrolidinyl]carbonyl]-N-(phenylmethyl)- I -pyrrolidinecarboxamide (JTP-4819). JTP-4819 strongly and specifically inhibited PEP activity in the rat brain (IC5o = 0.83 riM). Ex vivo enzyme activity studies showed that JTP-4819 (3 mg/kg, p.o,) inhibited PEP activity in the cerebral cortex, hippocampus, corpus striatum, and other brain regions of rats. JTP-4819 inhibited degradation of SP, AVP, and TRH by PEP in rat cortical and hippocampal supernatants with 1C5ovalues of the nanomolar order. Cortical and/or hippocampal SP-like immunoreactivity (SP-LI) and TRH-LI significantly decreased in aged rats. Administration of JTP-aRI9 (0.3 and/or 1 mg/kg, p.o.) for 21 days significantly reversed this decrease of SP-LI and TRH-LI. A study employing the Morris water maze task demonstrated that repeated administration of JTP-4819 (1.0 and/or 3 mg/kg, p.o.) ameliorated memory deficits in aged rats, rats with middle cerebral artery occlusion, and rats with nucleus basalis magnocellularis lesions. JTP-4819 (1-10 mg/kg, p.o.) also significantly prolonged the retention time in scopolamine-treated rats performing the passive avoidance task. Coadministration of JTP-4819 with S P, AVP, or TRH (at doses where each agent alone did not prolong retention) increased the retention time in scopolamine-treated rats, suggestingthe activation of peptidergic neurons. A microdialysis study demonstrated that JTP-4819 (3 mg/kg, p.o.) significantly increased ACh release in the frontal cortex and hippocampus of aged rats, suggesting the activation of cholinergic neurons. Recently, we found that JTP4819 inhibited 6-amyloid production by NGI08-15 cells, indicating that it might also slow the progression of Alzheimer's disease. Taken together, these pharmacological actions of .1TP-4819 suggest that it may be of therapeutic value for Alzheimer's disease.
344
Incidence of Alzhehner's Disease: The E U R O D E M Experience L.J. Lanner*, L.A. Amaducci, K. Andersen, J.F. Dartigues, P. Kragh-Sorensen, L. Letenneur, A. Lobo, J.M. Martinez-Lage, the MRC CFAS Study Group, A. Ott, A. HofnJan for the Eurodem Incidence Research Group There are few population-based studies of the incidence of dementing diseases. In particular incidence data on the most common form of dementing disease, Alzheimer's disease are lacking. Y e t such data are needed to identify risk factors for disease onset. EURODEM is a European Union funded network of centres involved in implementing population-based studies on epidemiology of dementing diseases, including Alzheimer's disease. The objectives of EURODEM are to (1) examine geographic variation in incidence rates of dementing diseases; (2) examine risk factors for incident dementing diseases. EURODEM studies include community-dwelling and institutionalized individuals aged 65 years and older. A two stage procedure is used to identify cases. This includes screening the total population on cognitive function, and performing a more detailed clinical assessment on screen positive respondents. Cases are reviewed by a EURODEM case review board, for consistency in diagnosis across the various centres. Data on a core set of risk factors collected by all studies. Currently, 570 cases have been identified including over 36,000 person-years in the context of five of the EURODEM studies. These studies are located in France (PAQUID Study), Denmark (Odense Study), the Netherlands (Rotterdam Study), and the United Kingdom (Medical Research Council Cognitive Function and Aging Study including the Liverpool MRC-Alpha Study). In this presentation we will give the age and sex stratified incident rates for all dementia and by sub-type for individual studies and for the total group.