VISUALIZING BRAIN A-BETA, TAU /SEROTONIN RECEPTOR DENSIT

该项目旨在开发一种全面的方法来显示活体阿尔茨海默病(AD)患者的AP(老年斑，SPS)和tau聚集体(神经原纤维缠结，NFTs)，并将重点放在体外和体外研究(如生化测量，放射自显影)，动物microPET和转基因啮齿动物的microMRI测定。动物模型为：(1)大鼠β-淀粉样变性三重突变转基因动物模型； (2)多西环素调控突变型人P301L tau转基因小鼠(RTg4510)模型的建立 (3)可诱导的海马神经元和皮质神经元丢失的白喉毒素转基因模型。Tau和Abeta聚集体的测定将与海马区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：目的1.研究动物模型中[18F]FDDNP的成像模式，以表征其在体内与不同类型的Abeta和tau沉积的结合，以探测信号随发病阶段的变化。通过 将[18F]FDDNP在Abeta和tau转基因啮齿动物中的标记模式与我们最终期望验证的[18F]FDDNP在活体PET患者中标记tau和AP的能力进行比较；目的2.在tau聚集的动物模型中测量大脑中5-HT1A受体的密度，并将突触素和神经元丢失与tau病理联系起来。在转基因Abeta和tau啮齿动物模型中测量的这些受体密度将与行为测量相关，并与[18F]FDDNP测量Abeta和缠结负荷、使用MicroMRI进行结构确定以及最终使用[18F]MPPF(5-HT1A受体配体)和[18F]FDDNP进行脑放射自显影相比较。我们最终希望验证我们的观察结果 AD患者活体脑内海马区5-HT1a受体密度与疾病严重程度呈负相关。我们假设，在tau转基因啮齿动物模型中，较低水平的5-HT1A受体密度将与神经元死亡有关，并与相同区域内[18F]FDDNP的积累呈负相关。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，将比仅使用一个探头的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。此外，[18F]FDDNP标记tau聚集体的能力将特别重要，因为在AD早期，tau聚集体与嗅下、内嗅皮质和海马神经元死亡以及记忆障碍之间的关系已经确立。它还将为早期发现AD(例如，有风险的患者)提供基础。

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).