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）： 40-60% 的阿尔茨海默病患者会出现精神病（阿尔茨海默病 + 精神病，AD+P）。与无精神病的 AD (AD-P) 相比，AD+P 与更严重的认知障碍以及更快的认知和功能恶化相关。我们和其他人已经证明 AD+P 在家族中聚集，表明它可能源于不同的潜在神经生物学。先前的研究表明，AD 患者认知障碍的最强相关因素是新皮质区域突触的丧失，其中树突棘上的兴奋性突触受到的影响尤其严重。最近，来自细胞培养、转基因小鼠和人体尸检的证据提供了一致的证据，表明可溶性淀粉样蛋白 β (A() 启动病理生理级联反应，导致 AD 中的突触破坏。可溶性 A( 可以通过改变平衡来导致脊柱损失棘内突触后信号传导从支持长期增强 (LTP) 的途径到支持长期抑制 (LTD) 的途径以及通过增加微管相关蛋白 tau 的聚集(MAPT)。这些发现表明，由于可溶性 A 的影响，AD+P 患者的认知过程恶化速度更快，反映出比无精神病的 AD 受试者 (AD-P) 更大程度的皮质突触破坏。 ( 和/或 A( 引起的脊柱功能障碍和丧失的下游效应器)。为了支持这一模型，我们之前报道了与 AD+P 受试者中多个新皮质区域的突触破坏增加一致的生化证据，并且初步数据表明可溶的AD+P 受试者与 AD-P 受试者相比，A(1-42 增加)。我们现在建议在现有 AD+P 和 AD-P 受试者队列的死后组织中进一步检查该模型。我们将检验以下假设：1) 相对于 AD-P 受试者，AD+P 受试者中可溶性 A(1-42) 浓度增加，而可溶性 A(1-40 浓度则不然)；2) AD+P 受试者中树突棘的数量和密度减少与患有 AD-P 的受试者相比，患有 AD+P 的受试者；3) 与患有 AD-P 的受试者相比，在 AD+P 中，LTP（Kalirin7 和 PAK1）的效应器减少，LTD（钙调磷酸酶）的效应器升高。 AD-P 科目； 4) 相对于 AD-P 受试者，AD+P 受试者中 MAPT 聚集增加。这些因素的相互关系将通过探索性分析来检验，以检验它们的独立影响和中介影响。计划中的研究是新颖的，并且受益于高质量的脑组织资源，其中所有受试者都接受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。成功完成计划的分析将告知是否：1）AD+P 受试者新皮质中的树突棘过度丢失； 2)脊柱损失的程度与可溶性A的浓度相关(或者，3)与聚集的MAPT和/或结构LTP和LTD介体的浓度相关。该知识库将用于生成有关导致 AD+P 突触过度破坏的因果途径的机制假设，这些假设可以在未来的研究中使用其他动物和/或体外实验模型进行测试。 公共卫生相关性： 设施和其他资源 Highland Drive 校区 B4R207W - 240 平方米英尺，B4R229SW - 910 平方米英尺； Sweet 博士位于匹兹堡大学生物医学科学塔 (BST) 楼层的实验室（W1603、W1604、W1606）附加了部分场外豁免。生物医学科学塔 (BST) 内的实验室面积约为 2,800 平方英尺，可供该项目使用。实验室由用于组织固定和制备、免疫细胞化学和其他组织学程序、蛋白质印迹以及计算机辅助显微镜和图像分析的独立设施组成。计算机 实验室配备了以下计算机： Dell PowerEdge 4400，配备双 733 MHz Xeon 处理器 Novell Server，用于维护脑标本数据库并运行 Web 服务器。它还用作文件服务器。四个 Dell Precision 工作站，频率范围从 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、三台 2.0 至 3.1 GHz 范围的 Pentium IV 计算机2.4 GHz 范围，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；十台惠普黑白激光打印机；富士 Pictrography 3000 打印机。办公室 Sweet 博士在 Highland Drive 园区拥有共享办公空间，其中还设有数据经理的办公室。博士。 Sweet、Ikonomovic 和 Fish 的办公室位于生物医学科学塔 (BST) 的实验室附近。其他共用组织学实验室、暗室、冷藏室、低温冷冻室、小动物灌注室、设备室和玻璃清洗设施也位于BST 16层。位于克劳福德大厅的机器和电子商店可供转化神经科学项目的教员使用。