PDE is a supeffamily of enzymes that break down the important second messengers cyclic AMP （cAMP） PDE4 is the most important fami- and cyclic GMP （cGMP）. There are 11 PDE families （ PDEI-11 ） ; among them, ly i...PDE is a supeffamily of enzymes that break down the important second messengers cyclic AMP （cAMP） PDE4 is the most important fami- and cyclic GMP （cGMP）. There are 11 PDE families （ PDEI-11 ） ; among them, ly in the control of intracellular cAMP signaling. It has been established that PDE4 is an essential player in the me- diation of AD and alcoholism. Chronic alcohol consumption can cause alcohol-related dementia and 50% - 75% of detoxified alcoholics have memory or cognition impairment. The lecture will focus on the unique role of PDE4 and its isoforms （PDE4A-D） in mediating AD and alcoholism and the cellular mechanisms involved. Specifically, using mice deficient in PDE4A, PDE4B, or PDE4D, and their wild type （WT） controls, it was found that PDE4Adeficiencydecreased alcohol intake and preference and reversed Abeta42-induced memory deficits. In con- trast, deficiency of PDE4B only mimicked the ability of PDE4A-deficiency to reduce alcohol consumption, while deficiency of PDE4D only reversed Abeta42-induced memory deficits. In addition, levels of cAMP and phospho- CREB （pCREB） were increased in the hippocampus of mice deficient in PDE4A or PDE4D, which also produced reversal of Abeta42-induced decreases in pCREB. These datasuggest that PDE4 isoforms have different roles in me-diating alcohol-drinking behavior and memoryin Alzheimer＇ s disease, which are mediated by cAMP/CREB signa- ling. The results indicate PDE4A as a potential new target for alcohol-related dementia, although studies with ani- mal models of alcohol-related dementia are needed to clarify this.展开更多
Classical inhibitors of PDE4 lack subtype selectivity due to exact amino acid sequence conservation of the catalytic site,and consequently,development of these drugs has stalled due to dose-limiting side effects of na...Classical inhibitors of PDE4 lack subtype selectivity due to exact amino acid sequence conservation of the catalytic site,and consequently,development of these drugs has stalled due to dose-limiting side effects of nausea and emesis.While use of subtype-selective inhibitors(i.e.,for PDE4A,B,or D)could overcome this issue,conservation of the catalytic region,to which classical inhibitors bind,limits this approach.The present study examined the effects of BPN14770,an allosteric inhibitor of PDE4D,which binds to a primate-specific,N-terminal region,conferring greater than 260-fold selectivity for PDE4D.BPN14770 was 100-fold more potent for improving memory and cognition in humanized PDE4D(hPDE4D)mice,which expressed the primate-specific binding sequence,compared to wild-type mice;meanwhile,it exhibited low potency in a mouse surrogate model for emesis.The behavioral and matching neurochemical data presented established a relationship between PDE4D target engagement and effects on cognition for BPN14770.Furthermore,BPN14770 reversed memory and cognitive deficits induced byβ-amyloid peptide 1-42(Aβ42)in Morris water maze,Y maze and novel object recognition tests in the humanized PDE4D mice.The morphological analyses suggested that the number of dendrites and the dendritic length in the CA1 of hippocampus were significantly increased after the Aβ42-treated hPDE4D mice were administered of BPN14770 for two weeks.The neurochemical and molecular biological assays suggested that neuroplasticity-related proteins and neurotrophic factor BDNF in the hippocampus of hPDE4D mice were significantly increased after the hPDE4D mice were treated with BPN14770.These findings suggest clinical potential for PDE4D selective inhibitors in disorders with cognitive deficits such as Alzheimer’s disease,which affects approximately 20 million people worldwide and nearly 5 million people in the United States.展开更多
目的:在缺血性卒中家系中探讨PDE4D基因rs966221位点多态性与缺血性卒中及其相关性状的关系。方法:采用家系研究设计,应用广义估计方程(generalized estimating equation,GEE)进行多因素的回归分析,并用非参数连锁分析和以家系为基础的...目的:在缺血性卒中家系中探讨PDE4D基因rs966221位点多态性与缺血性卒中及其相关性状的关系。方法:采用家系研究设计,应用广义估计方程(generalized estimating equation,GEE)进行多因素的回归分析,并用非参数连锁分析和以家系为基础的关联检验(family based association test,FBAT)进行连锁和关联分析。结果:共纳入276个缺血性卒中家系,776名研究对象。应用GEE控制混杂因素并调整家系内部相关性后,载脂蛋白B、颈动脉内膜中层厚度、高密度脂蛋白胆固醇及血压水平与缺血性卒中相关(P<0.05)。非参数连锁分析和FBAT分析均未发现rs966221位点多态性与缺血性卒中相关,但该位点与卒中相关的数量性状存在连锁和关联关系。非参数连锁分析发现,在调整可能的混杂因素后,rs966221位点与载脂蛋白B(P<0.001)、超敏C反应蛋白水平(P=0.003)、收缩压(P=0.036)存在连锁;在调整高脂血症、高血压等疾病的患病状态后,rs966221位点TT基因型(P=0.019)和CT基因型(P=0.007)与颈动脉内膜中层厚度相关,显性模型中C等位基因与颈动脉内膜中层厚度具有统计学关联(P=0.019)。结论:血脂、血压的异常以及颈动脉内膜中层增厚与缺血性卒中相关,PDE4D基因rs966221位点与载脂蛋白B、超敏C反应蛋白及收缩压水平存在连锁,该位点C等位基因与颈动脉内膜中层厚度具有统计学关联。展开更多
文摘PDE is a supeffamily of enzymes that break down the important second messengers cyclic AMP （cAMP） PDE4 is the most important fami- and cyclic GMP （cGMP）. There are 11 PDE families （ PDEI-11 ） ; among them, ly in the control of intracellular cAMP signaling. It has been established that PDE4 is an essential player in the me- diation of AD and alcoholism. Chronic alcohol consumption can cause alcohol-related dementia and 50% - 75% of detoxified alcoholics have memory or cognition impairment. The lecture will focus on the unique role of PDE4 and its isoforms （PDE4A-D） in mediating AD and alcoholism and the cellular mechanisms involved. Specifically, using mice deficient in PDE4A, PDE4B, or PDE4D, and their wild type （WT） controls, it was found that PDE4Adeficiencydecreased alcohol intake and preference and reversed Abeta42-induced memory deficits. In con- trast, deficiency of PDE4B only mimicked the ability of PDE4A-deficiency to reduce alcohol consumption, while deficiency of PDE4D only reversed Abeta42-induced memory deficits. In addition, levels of cAMP and phospho- CREB （pCREB） were increased in the hippocampus of mice deficient in PDE4A or PDE4D, which also produced reversal of Abeta42-induced decreases in pCREB. These datasuggest that PDE4 isoforms have different roles in me-diating alcohol-drinking behavior and memoryin Alzheimer＇ s disease, which are mediated by cAMP/CREB signa- ling. The results indicate PDE4A as a potential new target for alcohol-related dementia, although studies with ani- mal models of alcohol-related dementia are needed to clarify this.
文摘Classical inhibitors of PDE4 lack subtype selectivity due to exact amino acid sequence conservation of the catalytic site,and consequently,development of these drugs has stalled due to dose-limiting side effects of nausea and emesis.While use of subtype-selective inhibitors(i.e.,for PDE4A,B,or D)could overcome this issue,conservation of the catalytic region,to which classical inhibitors bind,limits this approach.The present study examined the effects of BPN14770,an allosteric inhibitor of PDE4D,which binds to a primate-specific,N-terminal region,conferring greater than 260-fold selectivity for PDE4D.BPN14770 was 100-fold more potent for improving memory and cognition in humanized PDE4D(hPDE4D)mice,which expressed the primate-specific binding sequence,compared to wild-type mice;meanwhile,it exhibited low potency in a mouse surrogate model for emesis.The behavioral and matching neurochemical data presented established a relationship between PDE4D target engagement and effects on cognition for BPN14770.Furthermore,BPN14770 reversed memory and cognitive deficits induced byβ-amyloid peptide 1-42(Aβ42)in Morris water maze,Y maze and novel object recognition tests in the humanized PDE4D mice.The morphological analyses suggested that the number of dendrites and the dendritic length in the CA1 of hippocampus were significantly increased after the Aβ42-treated hPDE4D mice were administered of BPN14770 for two weeks.The neurochemical and molecular biological assays suggested that neuroplasticity-related proteins and neurotrophic factor BDNF in the hippocampus of hPDE4D mice were significantly increased after the hPDE4D mice were treated with BPN14770.These findings suggest clinical potential for PDE4D selective inhibitors in disorders with cognitive deficits such as Alzheimer’s disease,which affects approximately 20 million people worldwide and nearly 5 million people in the United States.
文摘目的:在缺血性卒中家系中探讨PDE4D基因rs966221位点多态性与缺血性卒中及其相关性状的关系。方法:采用家系研究设计,应用广义估计方程(generalized estimating equation,GEE)进行多因素的回归分析,并用非参数连锁分析和以家系为基础的关联检验(family based association test,FBAT)进行连锁和关联分析。结果:共纳入276个缺血性卒中家系,776名研究对象。应用GEE控制混杂因素并调整家系内部相关性后,载脂蛋白B、颈动脉内膜中层厚度、高密度脂蛋白胆固醇及血压水平与缺血性卒中相关(P<0.05)。非参数连锁分析和FBAT分析均未发现rs966221位点多态性与缺血性卒中相关,但该位点与卒中相关的数量性状存在连锁和关联关系。非参数连锁分析发现,在调整可能的混杂因素后,rs966221位点与载脂蛋白B(P<0.001)、超敏C反应蛋白水平(P=0.003)、收缩压(P=0.036)存在连锁;在调整高脂血症、高血压等疾病的患病状态后,rs966221位点TT基因型(P=0.019)和CT基因型(P=0.007)与颈动脉内膜中层厚度相关,显性模型中C等位基因与颈动脉内膜中层厚度具有统计学关联(P=0.019)。结论:血脂、血压的异常以及颈动脉内膜中层增厚与缺血性卒中相关,PDE4D基因rs966221位点与载脂蛋白B、超敏C反应蛋白及收缩压水平存在连锁,该位点C等位基因与颈动脉内膜中层厚度具有统计学关联。
