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: 7434496
• 负责人: JORGE R BARRIO
• 金额: $ 21.03万
• 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/7434496
• 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

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综合方法，用于可视化活体阿尔茨海默病 (AD) 患者的 Ap（老年斑，SP）和 tau 聚集体（神经原纤维缠结，NFT），并将重点关注体外和离体研究（例如生化测量） 、放射自显影）、转基因啮齿动物的动物 microPET 和 microMRI 测定。动物模型为：(1)β-淀粉样变性大鼠三突变体转基因模型； (2)强力霉素调节的突变型人P301L tau转基因小鼠（rTG4510系）模型 伴有缠结和神经元损失； (3)用于分级海马和皮质神经元损失的诱导白喉毒素转基因模型。 tau 和 Abeta 聚集体的测定将与海马中的 5-HT1A 密度相关，作为神经元死亡的衡量标准和疾病进展的指标。具体目标如下： 目标 1. 研究动物模型中的 [18F]FDDNP 成像模式，以表征其与不同 Abeta 和 tau 沉积物类型的体内结合，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，我们最终希望验证 [18F]FDDNP 在活体 PET 患者中标记 tau 和 Ap 的能力；目标 2. 在 tau 聚集动物模型中测量整个大脑的 5-HT1A 受体密度，并将突触素和神经元损失与 tau 病理学相关联。在转基因 Abeta 和 tau 啮齿动物模型中体内测量的这些受体密度将与行为测量相关，并与 Abeta 和缠结负荷的 [18F]FDDNP 测量、microMRI 的结构测定以及最终使用 [18F]MPPF (5-HT1A) 的脑放射自显影进行比较。受体配体）和[18F]FDDNP。我们最终希望验证我们的观察结果 AD 患者的活体大脑海马 5-HT1A 受体密度与疾病严重程度呈负相关。我们假设 tau 转基因啮齿动物模型中较低水平的 5-HT1A 受体密度与神经元死亡有关，并与相同区域的 [18F]FDDNP 积累呈负相关。在人类研究中，将这些测量与同一患者的局部脑葡萄糖代谢率测定相结合，将比仅使用一个探针的 PET 测量更有效地区分轻度认知障碍 (MCI) 患者和认知正常对照患者。此外，[18F]FDDNP 标记 tau 聚集的能力尤其重要，因为 tau 聚集、内嗅下、内嗅皮质和海马神经元死亡以及早期 AD 记忆缺陷之间已建立关系。它还将为 AD 的早期检测（例如，处于危险中的患者）提供基础。