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

项目总结/摘要 在这项资助申请中，我们提出开发和验证最佳的18F标记的σ-1（σ1）受体 用于阿尔茨海默病（AD）转化研究的放射性配体，以进一步阐明σ1受体在阿尔茨海默病中的作用。 AD发病机制和进展，以探讨AD动物模型中σ1受体的纵向变化，沿着 与突触生物标志物突触囊泡蛋白2A（SV 2A）和AD病理生物标志物b-淀粉样蛋白（Ab） 探讨σ1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，在美国困扰着600万人。从诊断 从这个角度来看，AD越来越被沿着一个从临床前AD到轻度认知障碍的连续体来看待 (MCI)和AD痴呆。AD的临床痴呆与一种独特的病理学有关， 由b-淀粉样蛋白（Ab）、过度磷酸化的tau蛋白的神经元缠结和突触丢失组成。 然而，AD发病机制的分子机制是复杂的，仍然难以捉摸。几 已经提出了一些假说，包括β-淀粉样蛋白假说，错误折叠的tau蛋白假说， 胆碱能假说，以及氧化应激和钙稳态异常的参与。前 斑块和缠结的积累，生物化学和形态学变化，如钙的改变， 胆固醇和脂质代谢，改变线粒体动力学，减少生物能量相互作用，都是 与定位于内质网（ER）的功能密切相关 膜（MAMs）。σ1受体位于MAM。最近的研究发现， AD中最早的Ab产生到MAM中的神经元，以及σ1受体对其的关键调节，从而 证实了σ1受体在AD发病机制中的中心作用。因此，σ1受体被认为是 AD治疗发展的重要靶点。作为线粒体功能的替代标志物， 作为MAM上Ab产生的调节剂，它也有很大的希望作为诊断AD的生物标志物， 最早的阶段 这项申请中提出的研究将弥合对σ1受体理解的重要空白 利用耶鲁大学在新型PET方面的独特专业知识和经验， 放射性配体开发、AD机制研究和治疗靶点鉴定。σ1的研究 在AD动物模型中，与突触密度、Ab和tau的生物标志物纵向相关的受体是一种 我们正在进行的研究的自然延伸。完成后，该项目将提供进一步的见解， AD的病因学，并帮助确定早期AD诊断的最敏感和有效的生物标志物， 用于监测疾病进展和新兴AD疗法的疗效。

Project Summary/Abstract 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.