Cortical Synapses and Psychosis in AD

描述(由申请人提供)： 40%-60%的阿尔茨海默病(阿尔茨海默病+精神病，AD+P)受试者会发生精神病。与无精神病的AD(AD-P)相比，AD+P与更大的认知损害和更快的认知和功能退化有关。我们和其他人已经证明AD+P在家族中聚集，表明它可能源于一种不同的潜在神经生物学。先前的研究表明，阿尔茨海默病患者认知障碍的最强相关性是新皮质区域的突触丢失，其中树突棘上的兴奋性突触受到的影响尤为严重。最近，来自细胞培养、转基因小鼠和死后人类研究的证据表明，可溶性淀粉样β蛋白(A())启动了导致AD突触破坏的病理生理学级联反应。通过将突触后信号的平衡从支持长期增强(LTP)的途径转移到支持长期抑制(LTD)的途径，以及通过增加微管相关蛋白tau(MAPT)的聚集，可导致脊柱丢失。这些发现提示了一种模型，在该模型中，患有AD+P的个体的认知过程更迅速地恶化，反映了比没有精神病的AD受试者(AD-P)更严重的皮质突触破坏程度，这是由于可溶性A(和/或A(引起的脊椎功能障碍和丢失的下游效应因子)的影响。为了支持这一模型，我们之前已经报道了与AD+P受试者多个新皮质区域突触破坏增加一致的生化证据，并有初步数据表明，与AD-P受试者相比，AD+P受试者sA(1-42)增加。我们现在建议在AD+P和AD-P的现有队列中的尸检组织中进一步研究这一模型。我们将检验以下假设：1)与AD-P组相比，AD+P组的可溶性A(1-42)浓度增加，而可溶性A(1-40)浓度不变；2)AD+P组与AD-P组相比，树突棘的数量和密度减少；3)LTP(Kalirin7和PAK1)的效应器减少，LTD(钙调神经磷酸酶)的效应器升高；4)AD+P组相对于AD-P组存在MAPT聚集增加。这些因素的相互关系将在探索性分析中加以审查，以检验它们的独立和中介作用。计划中的研究是新颖的，并受益于获得高质量的脑组织资源，其中所有受试者都接受了最先进的标准化临床和神经病理评估，包括结构化的精神病生前行为评估。计划分析的成功完成将告诉我们：1)AD+P受试者的新皮质中是否存在树突棘的过度丢失；2)脊椎丢失的程度与可溶性A的浓度相关(或者，3)与聚集的MAPT和/或结构LTP和LTP的介体的浓度相关。这个知识库将用于产生关于导致AD+P过度突触破坏的因果路径的机制假说，这些假说可以在未来的研究中使用更多的动物和/或体外实验模型进行验证。 公共卫生相关性： 设施及其他资源高地大道校区B4R207W-240平方米。英尺，B4R229SW-910平方英尺英国《金融时报》；斯威特博士的实验室(W1603、W1604、W1606)的部分非现场豁免附在匹兹堡大学生物医学科学塔(BST)的地板上。实验室面积约2800平方英尺英国《金融时报》在生物医学科学塔(BST)可用于该项目。这些实验室包括独立的设施，用于组织固定和准备、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。计算机实验室配备了以下计算机：配备双733 MHz至强处理器Novell服务器的Dell PowerEdge 4400，用于维护脑组织标本数据库和运行Web服务器。它还用作文件服务器。4台Dell Precision工作站，范围从800 MHz奔腾III到2.2 GHz奔腾IV；1台奔腾II计算机，6台400 MHz到866 MHz范围的奔腾III计算机；2台1到2 GHz范围的奔腾III计算机；20台2.0到3.1 GHz范围的奔腾IV计算机；以及3台2.0到2.4 GHz范围的奔腾IV计算机，用于一般用途和成像。爱克发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Pictrograph 3000打印机。办公室斯威特博士在高地大道校区共享办公空间，数据经理的办公室也设在那里。斯威特博士、伊科诺莫维奇博士和菲什博士的办公室毗邻他们在生物医学科学塔(BST)的实验室。其他A共用的组织学实验室、暗室、冷藏室、低温冷冻室、小动物灌注室、设备间和玻璃清洗设施也位于BST的16楼。机器和电子商店位于克劳福德大厅，可供翻译神经科学项目的教职员工使用。

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.