VISUALIZING BRAIN A-BETA, TAU AND SEROTONIN RECEPTOR DENSITIES

可视化大脑 A-β、TAU 和血清素受体密度

• 批准号: 7629724
• 负责人: JORGE R BARRIO
• 金额: $ 21.23万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7629724
• 关键词: Alzheimer' s Disease; Amyloid beta-Protein; Amyloidosis; Animal Model; Animals; Area; Autopsy; Autoradiography; Binding; Biochemical; Brain; Cerebrum; Cessation of life; Data; Dementia; Deposition; Diphtheria Toxin; Disease Progression; Doxycycline; Early Diagnosis; Glucose; Hippocampus (Brain); Human; Image; In Vitro; Individual; Investigation; Label; Lesion; Life; Ligands; Measures; Medial; Memory impairment; Metabolic; Modeling; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathology; Patients; Pattern; Rate; Rattus; Research; Risk; Rodent; Rodent Model; Scanning; Senile Plaques; Serotonin Receptor 5-HT1A; Severity of illness; Signal Transduction; Staging; Synaptophysin; Transgenic Animals; Transgenic Mice; Transgenic Model; Transgenic Organisms; base; behavior measurement; density; entorhinal cortex; in vivo; mild neurocognitive impairment; mutant; neuron loss; normal aging; receptor density; serotonin 5 receptor; serotonin receptor; tau Proteins; tau aggregation; Alzheimer' s Disease; Amyloid beta-Protein; Amyloidosis; Animal Model; Animals; Area; Autopsy; Autoradiography; Binding; Biochemical; Brain; Cerebrum; Cessation of life; Data; Dementia; Deposition; Diphtheria Toxin; Disease Progression; Doxycycline; Early Diagnosis; Glucose; Hippocampus (Brain); Human; Image; In Vitro; Individual; Investigation; Label; Lesion; Life; Ligands; Measures; Medial; Memory impairment; Metabolic; Modeling; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathology; Patients; Pattern; Rate; Rattus; Research; Risk; Rodent; Rodent Model; Scanning; Senile Plaques; Serotonin Receptor 5-HT1A; Severity of illness; Signal Transduction; Staging; Synaptophysin; Transgenic Animals; Transgenic Mice; Transgenic Model; Transgenic Organisms; base; behavior measurement; density; entorhinal cortex; in vivo; mild neurocognitive impairment; mutant; neuron loss; normal aging; receptor density; serotonin 5 receptor; serotonin receptor; tau Proteins; tau aggregation

This project intends to develop a comprehensive approach for visualizing Ap (senile plaques, SPs) and tau aggregates (neurofibrillary tangles, NFTs) in the living Alzheimer's disease (AD) patient, and will focus on in vitro and ex vivo studies (e.g.biochemical measures, autoradiography), animal microPET and microMRI determinations in transgenic rodents. The animal models are: (1) a rat triple mutant transgenic model for beta-amyloidosis; (2) a doxycycline regulated mutant human P301L tau transgenic mouse (line rTG4510) model with tangles and neuronal loss; and (3) an inducible diphtheria toxin transgenic model for graded hippocampal and cortical neuronal loss. Determination of tau and Abeta aggregates would be correlated with 5-HT1A densities in hippocampus as a measure of neuronal death and an indicator of disease progression. Specific Aims are as follows: Aim 1. To investigate [18F]FDDNP imaging patterns in animals models to characterize its in vivo binding to different Abeta and tau deposit types to probe signals as a function of pathogenic stage. By comparing [18F]FDDNP labeling patterns in Abeta and tau transgenic rodents with we ultimately expect to validate the ability of [18F]FDDNP to label tau and Ap in living patients with PET; and Aim 2. To measure 5-HT1A receptor densities throughout the brain in animal models of tau aggregation and correlate synaptophysin and neuronal loss with tau pathology. These receptor densities measured in vivo in transgenic Abeta and tau rodent models will be related to behavioral measures and compared with [18F]FDDNP measures of Abeta and tangle burden, structural determinations with microMRI and ultimately brain autoradiography using [18F]MPPF (5-HT1A receptor ligand) and [18F]FDDNP. We ultimately expect to validate our observations in the living brain of AD patients that 5-HT1A receptor densities in hippocampus are inversely correlated to disease severity. We hypothesize that lower levels of 5-HT1A receptor densities in tau transgenic rodent models will be related to neuronal death and correlate negatively with [18F]FDDNP accumulation in the same areas. In human research combining these measures with regional cerebral glucose metabolic rate determinations in the same patients will more efficiently differentiate patients with mild cognitive impairment (MCI) and cognitively normal controls than PET measures with only one probe. Moreover, the ability of [18F]FDDNP to label tau aggregates would be particularly important because of the established relationship between tau aggregates, neuronal death in subentorhinal, entorhinal cortices and hippocampus, and memory deficits in early AD. It will also provide the basis for early detection of AD (e.g., patients at risk).

该项目旨在开发一种可视化AP（老年斑块，SP）和Tau聚集体（神经原纤维缠结，NFT，NFT）的全面方法，并将重点介绍体内和体内研究（例如，自动化型，自动摄像机），动物微元素和微型计算。动物模型是：（1）β-淀粉样变性的大鼠三重突变转基因模型； （2）强力霉素调节的突变体人P301L TAU转基因小鼠（线RTG4510）模型 缠结和神经元丧失； （3）用于分级海马和皮质神经元丧失的诱导型白喉转基因模型。 TAU和ABETA聚集体的测定将与海马中的5-HT1A密度相关，以衡量神经元死亡和疾病进展的指标。具体目的如下：目标1。在动物模型中研究[18F] FDDNP成像模式，以表征其与不同ABETA和TAU沉积类型的体内结合，以探测信号作为致病阶段的函数。经过 比较Abeta和Tau转基因啮齿动物中的[18F] FDDNP标记模式与我们最终希望验证[18F] FDDNP在活着的PET患者中标记Tau和AP的能力；和目标2。在TAU聚集的动物模型中测量整个大脑中的5-HT1A受体密度，并将突触possion蛋白和神经元丧失与Tau病理相关。这些在转基因Abeta和Tau啮齿动物模型中在体内测量的受体密度将与行为措施有关，并与[18F] FDDNP Abeta和Tangle负担的[18F] FDDNP测量，Micromri的结构测定以及最终使用[18F] MPPF（5-HT1A受体Ligand）和[18F] FD的结构性测定。我们最终希望验证我们的观察 AD患者的活体大脑，海马中5-HT1A受体密度与疾病的严重程度成反比。我们假设Tau转基因啮齿动物模型中的5-HT1A受体密度较低，将与神经元死亡有关，并与[18F] FDDNP在同一区域积累呈负相关。在将这些措施与同一患者的区域脑葡萄糖代谢率确定结合的人类研究中，将更有效地区分轻度认知障碍（MCI）和认知正常对照的患者，而仅与只有一项探针的PET度量相比。此外，由于[18F] FDDNP标记Tau聚集体的能力尤为重要，因为Tau聚集体，肠道下，内嗅皮层和海马的神经元死亡之间的既定关系以及早期AD的记忆缺陷。它还将为早期发现AD（例如有风险的患者）提供基础。