: The deposition of beta-sheet fibrils in Alzheimer's disease (AD) brain has been hypothesized to be the primary cause of this devastating neurodegenerative disease. These deposits include the amyloid-beta (Abeta) protein in plaques and vascular amyloid and hyper-phosphorylated tau protein in neurofibrillary tangles, dystrophic neurites and neuropil threads. Despite the presence of this characteristic neuropathology and its critical importance in the pathophysiology of the disease, no non-invasive technique has been validated to assess the presence of these deposits in living patients. The absence of such a technique hinders early and presymptomatic diagnosis and will severely hinder the development of immune therapies aimed at prevention or reversal of beta-sheet fibril deposition. Over the past decade, our laboratory has worked to develop an in vivo beta-sheet amyloid fibril imaging agent. This work has resulted in a promising lead agent, [N-methyl-11C]2(-4'-methylaminophenyl-benzothiazole (or [11C]BTA-1) which: 1) readily enters and clears from normal rodent and baboon brain; 2) binds to synthetic Abeta with nanomolar affinity; 3) specifically stains plaques and tangles in post-mortem AD brain; 4) binds to homogenates of post-mortem AD brain frontal cortex at >10-fold higher levels than aged control brain and non-AD demented brain samples, but shows no increased binding in AD cerebellum; and 5) shows no evidence of acute toxicity in preliminary studies. Furthermore, preliminary in vivo studies using APP transgenic mice and low resolution PET scanning show increased accumulation in the transgenic mice. In this study, we propose to validate the use of [11C]BTA-1 for in vivo amyloid imaging in PS/APP transgenic mice using a small animal microPET scanner. We will correlate in vivo results with: 1) quantitative immunohistochemical and histochemical measures of amyloid deposition; 2) Abeta ELISA; and 3) ex-vivo [11C]BTA-1 levels and post-mortem [3H]BTA-1 binding. We will show feasibility of longitudinal studies of the [11C]BTA-1/microPET technique in PS/APP mice and apply the technique to study an immune therapy protocol in these mice. Our goal is to provide a tool for use by investigators developing improved immune therapy protocols in transgenic mice, thus speeding progress in this area. However, because all of the techniques developed in this proposal apply directly to human studies, completion of this study will greatly speed the development of this technology for use in human studies of anti-amyloid therapies (immune therapy and secretase inhibitor therapies).
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