Sigma-1 Receptor Radioligand for Translational Research in Alzheimer's Disease

在这项拨款申请中，我们建议开发和验证一种最佳的18F标记的Sigma-1(σ1)受体 放射配基用于阿尔茨海默病(AD)的翻译研究以进一步阐明σ1受体在阿尔茨海默病中的作用 AD发病机制及进展，探讨AD动物模型中σ-1受体的纵向变化 突触生物标记物突触囊泡蛋白2A(SV2A)，以及AD病理生物标记物b-淀粉样蛋白(Ab)和 探讨σ-1受体显像在AD早期诊断中的应用价值。 AD是一种进行性退行性疾病，在美国有600万人深受其苦。从诊断结果来看 从角度来看，人们越来越多地从临床前AD到轻度认知障碍(MCI)， 还有老年痴呆症。阿尔茨海默病的临床痴呆症与一种独特的病理相关联，斑块由 B-淀粉样蛋白、过度磷酸化的tau蛋白的神经纤维缠结和突触丢失。然而， 阿尔茨海默病发病的分子机制(S)复杂，至今仍不清楚。已经提出了几个假设 提出了包括β-淀粉样蛋白假说、错误折叠tau蛋白假说、胆碱能假说、 氧化应激和钙代谢紊乱的参与。在斑块堆积之前 缠结，生化和形态的变化，如钙、胆固醇和脂肪代谢的变化， 线粒体动力学的改变和生物能量相互作用的减少都与功能密切相关 定位于线粒体相关的内质网(ER)膜(MAM)。σ-1受体是 位于MAM。最新的研究将AD中最早产生抗体的神经元定位为 σ-1受体的关键调控，从而证实了σ-1受体在AD中的中心作用 发病机制。因此，σ-1受体被认为是AD治疗发展的一个重要靶点。作为一名 线粒体功能的替代标记和抗体产生的调节，在MAM上也具有重要的意义 有望成为AD早期诊断的生物标志物。 这项申请中提出的研究将弥合对σ1受体理解的一个重要差距 利用耶鲁大学在新型PET领域的独特专业知识和经验，研究AD的发病和进展 放射配基发展，AD机制研究，治疗靶点识别。关于σ1的调查 在AD动物模型中，受体在纵向上与突触密度的生物标志物AB和tau有关，是一种天然的 扩展我们正在进行的研究。当项目完成时，该项目将提供对 AD的病因学，并帮助确定最敏感和有效的早期AD诊断的生物标志物，以及 监测疾病进展和新出现的阿尔茨海默病疗法的疗效。

In this grant application we propose to develop and validate an optimal 18F-labeled sigma-1 (σ1) receptor radioligand for translational research in Alzheimer’s disease (AD) to further elucidate the role of σ1 receptor in AD pathogenesis and progression, to probe longitudinal changes in σ1 receptor in AD animal models, along with the synapse biomarker synaptic vesicle protein 2A (SV2A), and AD pathologic biomarkers b-amyloid (Ab) and tau, and to explore the potential of σ1 receptor imaging for early diagnosis of AD. AD is a progressive degenerative disorder that afflicts 6 million people in the USA. From a diagnostic perspective, AD is increasingly viewed along a continuum from preclinical AD, to mild cognitive impairment (MCI), and to AD-dementia. The clinical dementia of AD is coupled to a distinct pathology, with plaques composed of b-amyloid (Ab), neurofibrillary tangles of hyperphosphorylated tau protein, and synaptic loss. However, the molecular mechanism(s) of AD pathogenesis is complex and remains elusive. Several hypotheses have been put forward, including the b-amyloid hypothesis, the misfolded tau protein hypothesis, the cholinergic hypothesis, and the involvement of oxidative stress and calcium dyshomeostasis. Before the accumulation of plaques and tangles, the biochemical and morphological changes, such as altered calcium, cholesterol, and lipid metabolism, altered mitochondrial dynamics, and reduced bioenergetic interaction, are all closely associated with functions localized to the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs). The σ1 receptor is situated at the MAM. The most recent research has located the earliest Ab generation in AD to neurons in the MAM, and its critical regulation by the σ1 receptor, thereby confirming the central role of σ1 receptor in AD pathogenesis. As such the σ1 receptor is considered an important target for AD therapeutic development. As a surrogate marker for mitochondria function and regulator of Ab production on the MAM, it also holds great promise as a biomarker for diagnosis of AD at its earliest stage. The research proposed in this application will bridge an important gap in the understanding of the σ1 receptor in AD pathogenesis and progression by leveraging the unique expertise and experience at Yale in novel PET radioligand development, AD mechanism study, and therapeutic target identification. Investigation of the σ1 receptor in AD animal models longitudinally in relation to biomarkers for synaptic density, Ab, and tau, is a natural extension of our ongoing research. When carried to completion, this project will provide further insights into the etiology of AD, and help identify a most sensitive and effective biomarker for early AD diagnosis, and for monitoring of disease progression and the efficacy of emerging AD therapies.