VISUALIZING BRAIN A-BETA, TAU AND SEROTONIN RECEPTOR DENSITIES

本项目旨在开发一种综合的方法来可视化阿尔茨海默病（AD）活体患者的Ap（老年斑，SPs）和tau聚集体（神经原纤维缠结，nft），并将重点放在转基因啮齿动物的体外和离体研究（如生化测量、放射自显影）、动物微pet和微mri测定上。动物模型为：(1)大鼠β -淀粉样变性三突变转基因模型；

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).