Cortical Synapses and Psychosis in AD

AD 中的皮质突触和精神病

• 批准号: 7691618
• 负责人: ROBERT A SWEET
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7691618
• 关键词: Abbreviations; Accounting; Address; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Animals; Antibodies; Area; Arts; Autopsy; Behavior assessment; Behavioral; Biochemical; Brain; Brain region; Calcineurin; Caregivers; Cell Culture Techniques; Clinical; Cognitive; Color; Complement; Computer Assisted; Computers; Data; Databases; Dementia; Dendritic Spines; Deterioration; Development; Diagnosis; Distress; Electronics; Equilibrium; Equipment; Event; Excitatory Synapse; Experimental Models; F-Actin; Faculty; Family; Figs - dietary; Fishes; Floor; Freezing; Functional disorder; Funding; Future; Future Generations; Genetic; Genetically Engineered Mouse; Health; Healthcare Systems; Heritability; Histology; Housing; Human; Image; Image Analysis; Impaired cognition; In Vitro; Individual; Internet; Intervention; Investigation; LIMK1 gene; Laboratories; Lasers; Lead; Long-Term Depression; Long-Term Potentiation; Magnetic Resonance Spectroscopy; Measures; Mediating; Mediator of activation protein; Membrane; Microscopy; Modeling; N-acetylaspartate; Neocortex; Neurobiology; Neurofibrillary Tangles; Pathology; Pathway interactions; Patient Care; Perfusion; Phenotype; Phospholipids; Phosphorylation; Prefrontal Cortex; Principal Investigator; Procedures; Protein Dephosphorylation; Psychotic Disorders; Relative (related person); Reporting; Research; Research Personnel; Resources; Risk; Role; Running; Sampling; Schizophrenia; Science; Signal Transduction; Specimen; Structure; Study Subject; Superior temporal gyrus; Synapses; Testing; Time; Tissue Fixation; Tissues; Toxic effect; Transgenic Mice; Universities; Vertebral column; Veterans; Western Blotting; Work; base; brain tissue; cofilin; cohort; cold temperature; cost; density; design; experience; gray matter; immunocytochemistry; indexing; knowledge base; neocortical; novel; programs; protein aggregate; spinophilin; synaptic function; tau Proteins; tau aggregation; tau mutation; tissue fixing; tissue preparation; tissue resource; translational neuroscience; waiver

DESCRIPTION (provided by applicant): Psychosis occurs in 40-60% of subjects with Alzheimer disease (Alzheimer disease + Psychosis, AD+P). AD+P is associated with greater cognitive impairment and more rapid cognitive and functional deterioration than in AD without psychosis (AD-P). We and others have shown that AD+P aggregates in families, indicating it may arise from a distinct underlying neurobiology. Prior studies have indicated that the strongest correlate of cognitive impairment in individuals with AD is loss of synapses across neocortical regions, with excitatory synapses onto dendritic spines particularly affected. Recently, evidence from cell culture, transgenic mice, and post-mortem human studies have provided converging evidence that soluble amyloid beta (A() initiates a pathophysiologic cascade leading to synapse disruption in AD. Soluble A( can cause spine loss by shifting the balance of post-synaptic signaling within spines from pathways supporting long-term potentiation (LTP) to those supporting long-term depression (LTD) and via increasing aggregation of microtubule-associated protein tau (MAPT). These findings suggest a model in which the more rapidly deteriorating cognitive course of individuals with AD+P reflects a greater degree of cortical synaptic disruption than found in AD subjects without psychosis (AD-P) due to the effects of soluble A( and/or downstream effectors of A(-induced spine dysfunction and loss. In support of this model, we have previously reported biochemical evidence consistent with increased synaptic disruption across multiple neocortical regions in subjects with AD+P, and have preliminary data indicating that soluble A(1-42 is increased in AD+P versus AD-P subjects. We now propose to further examine this model in postmortem tissue from an existing cohort of subjects with AD+P and AD-P. We will test the following hypothesis: 1) Soluble A(1-42 concentrations are increased in AD+P relative to AD-P subjects, while soluble A(1-40 is not; 2) Number and density of dendritic spines are reduced in subjects with AD+P in comparison to subjects with AD-P; 3) Effectors of LTP (Kalirin7 and PAK1) are reduced, and an effector of LTD (Calcineurin) is elevated, in AD+P compared to AD-P subjects; and 4) increased MAPT aggregation is present in AD+P relative to AD-P subjects. The inter- relationships of these factors will be examined in exploratory analyses examining their independent and mediating effects. The planned investigations are novel and benefit from access to a high quality brain tissue resource in which all subjects have undergone state-of-the- art standardized clinical and neuropathologic assessments, including structured antemortem behavioral assessments of psychosis. Successful completion of the planned analyses will inform whether: 1) there is excess loss of dendritic spines in neocortex of AD+P subjects; 2) the degree of spine loss is correlated with concentrations of soluble A(, or alternatively, 3) correlated with concentrations of aggregated MAPT and/or mediators of structural LTP and LTD. This knowledge base will serve to generate mechanistic hypotheses regarding the causal pathways resulting in excess synaptic disruption in AD+P that can be tested in future studies using additional animal and/or in vitro experimental models. PUBLIC HEALTH RELEVANCE: Facilities & Other Resources Highland Drive Campus B4R207W - 240Sq. ft., B4R229SW - 910Sq. ft.; Partial offsite waiver appended for Dr. Sweet's laboratories (W1603, W1604, W1606) in the floor of the Biomedical Science Tower (BST), University of Pittsburgh. Laboratory Approximately 2,800 sq. ft. is available for this project in the Biomedical Science Tower (BST). The laboratories consist of separate facilities for tissue fixation and preparation, immunocytochemistry and other histological procedures, western blotting, and computer-assisted microscopy and image analysis. Computer The laboratories are equipped with the following computers: Dell PowerEdge 4400 with dual 733 MHz Xeon processors Novell Server, used for maintaining the database of brain specimens and running the web server. It is also used as the file server. Four Dell Precision Workstations which range from an 800 MHz Pentium III to a 2.2 GHz Pentium IV; one Pentium II computer, six Pentium III computers in the 400 MHz to 866 MHz range, two Pentium III computers in the 1 to 2 GHz range, twenty Pentium IV computers in the 2.0 to 3.1 GHz range, and three Pentium IV computers in 2.0 to 2.4 GHz range, used for general use and imaging. AGFA Arcus Scanner and a Microtek ArtixScan 2500 Scanner. One Hewlett Packard color laser printer; ten Hewlett Packard black and white laser printers; Fuji Pictrography 3000 printer. Office Dr. Sweet has shared office space at the Highland Drive Campus, where an office for the data manager is also located. Drs. Sweet, Ikonomovic and Fish have offices located adjacent to their laboratories in the Biomedical Science Tower (BST). Other A shared histology laboratory, darkroom, coldroom, low temperature freezers, small animal perfusion room, equipment room and glasswashing facility are also located on the 16th floor of BST. Machine and electronic shops, housed in Crawford Hall, are available for the Translational Neuroscience Program faculty's use.

描述（由申请人提供）： 精神病发生在40-60%的阿尔茨海默病受试者中（阿尔茨海默病+精神病，AD+P）。与无精神病的AD（AD-P）相比，AD+P与更大的认知障碍和更快的认知和功能恶化相关。我们和其他人已经表明，AD+P聚集在家庭中，表明它可能来自一个独特的潜在神经生物学。先前的研究已经表明，AD患者中认知障碍的最强相关性是跨新皮层区域的突触丢失，其中树突棘上的兴奋性突触特别受影响。最近，来自细胞培养、转基因小鼠和死后人类研究的证据提供了一致的证据，即可溶性淀粉样蛋白β（A（））启动导致AD中突触破坏的病理生理级联反应。可溶性A（可通过将脊髓内突触后信号传导的平衡从支持长时程增强（LTP）的通路转移到支持长时程抑制（LTD）的通路以及通过增加微管相关蛋白tau（MAPT）的聚集来引起脊髓损失。这些发现表明了一种模型，其中AD+P个体的更快恶化的认知过程反映了比在无精神病的AD受试者（AD-P）中发现的更大程度的皮质突触破坏，这是由于可溶性A（和/或A（-诱导的脊柱功能障碍和丧失的下游效应物）的影响。为了支持这一模型，我们先前报道了与AD+P受试者中多个新皮层区域的突触破坏增加一致的生化证据，并且初步数据表明AD+P受试者中可溶性A β 1-42相对于AD-P受试者增加。我们现在建议在现有的AD+P和AD-P受试者队列的死后组织中进一步检查该模型。（1-42）AD+P组较AD-P组增加，而可溶性A（1-40）无增加;（2）AD+P组树突棘数目和密度较AD-P组减少; 3）与AD-P受试者相比，AD+P中LTP的效应物（Kalirin 7和PAK 1）减少，LTD的效应物（钙调磷酸酶）升高;和4）相对于AD-P受试者，AD+P中存在增加的MAPT聚集。这些因素的相互关系将在探索性分析中进行检查，以检查其独立和中介效应。计划的研究是新颖的，并受益于获得高质量的脑组织资源，其中所有受试者都经历了最先进的标准化临床和神经病理学评估，包括精神病的结构化生前行为评估。计划分析的成功完成将告知：1）AD+P受试者的新皮质中是否存在树突棘的过度损失;（2）脊髓缺失程度与可溶性A浓度相关（或者，3）与聚集的MAPT的浓度相关，和/或或结构LTP和LTD的介质。这一知识基础将有助于产生关于因果途径的机制假设，AD+P中的过度突触破坏，可以在未来的研究中使用额外的动物和/或体外实验模型进行测试。 公共卫生相关性： 设施与其他资源Highland Drive Campus B4 R207 W-240 Sq.英尺，B4 R229 SW-910平方米英尺; Sweet博士实验室（W1603、W1604、W1606）在匹兹堡大学生物医学科学塔（BST）楼层的部分场外豁免。实验室约2,800平方米英尺在生物医学科学塔（BST）中可用于此项目。实验室包括用于组织固定和制备、免疫细胞化学和其他组织学程序、蛋白质印迹法以及计算机辅助显微镜和图像分析的单独设施。计算机实验室配备了以下计算机：Dell PowerEdge 4400双733 MHz Xeon处理器Novell Server，用于维护大脑标本数据库和运行网络服务器。它也被用作文件服务器。四个Dell Precision工作站，范围从800 MHz Pentium III到2.2 GHz Pentium IV;一台Pentium II计算机，六台400 MHz至866 MHz范围的Pentium III计算机，两台1至2 GHz范围的Pentium III计算机，二十台2.0至3.1 GHz范围的Pentium IV计算机，以及三台2.0至2.4 GHz范围的Pentium IV计算机，用于一般用途和成像。AGFA Arcus扫描仪和Microtek ArtixScan 2500扫描仪。一台惠普彩色激光打印机;十台惠普黑白白色激光打印机; Fuji Pictrography 3000打印机。办公室甜博士在高地驱动器校园共享办公空间，那里也是数据经理的办公室。Sweet博士、Ikonomovic博士和Fish博士的办公室位于生物医学科学塔（BST）的实验室附近。其他共用的组织学实验室、暗室、冷藏室、低温冰柜、小动物灌注室、设备室和玻璃清洗设施也位于BST的16楼。位于克劳福德大厅的机器和电子商店可供翻译神经科学项目教师使用。