Tangle propagation in preclinical AD

临床前 AD 中的缠结传播

• 批准号: 8637372
• 负责人: Scott E Counts
• 金额: $ 20.52万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637372
• 关键词: AMPA Receptors; Affect; Alzheimer' s Disease; Apolipoprotein E; Arousal; Attention; Autopsy; Biochemistry; Biogenesis; Calcium; Cell Count; Cells; Cessation of life; Chemicals; Clinical; Cognition; Cognitive; Custom; DSP 4; Data; Deafferentation procedure; Dementia; Diagnostic; Disease; Down-Regulation; Employee Strikes; Episodic memory; Epitopes; Etiology; Event; Exhibits; Fiber; Functional disorder; Gene Expression; Genotype; Hippocampus (Brain); Homeostasis; Impaired cognition; Individual; Laboratories; Lentivirus Vector; Lesion; Link; Measures; Medial; Mediating; Memory; Microarray Analysis; Mitochondria; Modeling; Molecular; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Norepinephrine; Onset of illness; Pathogenesis; Pathology; Pathway Analysis; Pathway interactions; Pattern; Pilot Projects; Prevention; Prosencephalon; Proteins; RNA; Regulation; Research; Role; Sampling; Site; Source; Staging; Synapses; System; Temporal Lobe; Testing; Therapeutic; Time; Tissue Harvesting; Tissues; Transcript; Varicosity; base; clinical Diagnosis; cytochrome c oxidase; density; frontal lobe; human tissue; in vivo; insight; locus ceruleus structure; mild cognitive impairment; morphometry; nerve supply; neurofibrillary tangle formation; neuron loss; neuronal excitability; noradrenergic; novel; nuclear respiratory factor; pre-clinical; public health relevance; relating to nervous system; release of sequestered calcium ion into cytoplasm; spatiotemporal; transcription factor

DESCRIPTION (provided by applicant): This proposal will provide the first cellular and molecular mechanistic profile of noradrenergic locus coeruleus (LC) projection system loss during the preclinical course of AD. LC neurons provide the sole source of norepinephrine (NE) to the hippocampus/medial temporal lobe (MTL) and cortex, where they regulate memory, attention and arousal. Notably, these cells are likely the initial site of neurofibrillary tagle (NFT) formation, suggesting that progressive LC neurodegeneration may help drive NFT formation in its target fields. However, the extent to which LC vulnerability impacts the onse of disease is unclear. Our preliminary studies show that LC neurons from subjects who died with amnestic mild cognitive impairment (aMCI) display significant cell loss compared to control subjects and that noradrenergic fiber density is selectively reduced in the hippocampus compared to cortical target fields during aMCI. These data suggest that selective LC neuronal loss and noradrenergic deafferentation of the hippocampus is a pathogenic preclinical event underlying the transition from normal cognition to prodromal AD. To understand the role of LC system degeneration in AD etiology, we will quantify LC cell loss and fiber density within the MTL and frontal cortex using rarely acquired cases of individuals who displayed no cognitive impairment at the time of death, but who were found to have moderate to high Braak scores that are predictive of AD; these cases are the tissue equivalent of a "pre- MCI" condition called preclinical AD (PCAD). Whether LC fiber loss directly impacts NFT formation in MTL target fields is unclear. Pilot studies in our laboratory revealed that chemical lesioning of the LC wth the compound DSP4 increased NFT pathology in hippocampal CA1 neurons of the 3xTg-AD mouse, providing novel mechanistic evidence that LC degeneration propagates NFT pathology. To explore this mechanism, we used custom microarrays to analyze gene expression differences in CA1 neurons microdissected from control and DSP4-treated 3xTg-AD mice. Quantitative analysis revealed that noradrenergic deafferentation in DSP4-treated mice resulted in a pronounced 80% down- regulation of the transcription factor nuclear respiratory factor 1 (NRF1) in CA1 neurons. Moreover, pathway analysis unveiled a striking pattern wherein several NRF1 transcriptional targets were also down-regulated, including functional classes of transcripts regulating calcium-mediated neuronal excitabilit (e.g., GluR2 AMPA receptor) and mitochondrial biogenesis (e.g., cytochrome oxidase V). Subsequent pilot studies showed that NRF1 expression is tightly regulated by NE and that NRF1 is selectively reduced in the hippocampus compared to frontal cortex in aMCI subjects, tracking with the pattern of LC deafferentation. Therefore, our hypothesis is that LC projection system degeneration potentiates NFT pathology in MTL neurons during PCAD by disrupting NRF1-mediated calcium and mitochondrial homeostasis. To gain a better understanding of the effects of NE depletion on MTL neurofibrillary degeneration during the preclinical course of AD, we will combine in vivo manipulations of the 3xTg-AD mouse with exploratory microarray and pathway analysis of CA1 neurons. Altogether, this proposal will advance our understanding of fundamental mechanisms underlying multisystem deafferentation within the LC-MTL memory circuit, resulting in new information about disease etiology and new targets for timely diagnostic and therapeutic approaches.

描述（由申请方提供）：该提案将首次提供AD临床前病程期间去甲肾上腺素能蓝斑（LC）投射系统丧失的细胞和分子机制概况。LC神经元为海马/内侧颞叶（MTL）和皮质提供去甲肾上腺素（NE）的唯一来源，在那里它们调节记忆、注意力和唤醒。值得注意的是，这些细胞很可能是神经元标记（NFT）形成的初始位点，这表明进行性LC神经变性可能有助于驱动其靶区域中的NFT形成。 然而，LC脆弱性对疾病本身的影响程度尚不清楚。 我们的初步研究表明，LC神经元从受试者谁死于遗忘型轻度认知障碍（aMCI）显示显着的细胞损失相比，对照组和去甲肾上腺素能纤维密度选择性降低海马相比，皮层靶领域在aMCI。 这些数据表明，选择性LC神经元的损失和去甲肾上腺素能传入的海马是一个致病的临床前事件的基础从正常认知到前驱AD的过渡。为了了解LC系统变性在AD病因学中的作用，我们将使用在死亡时没有表现出认知障碍但被发现具有预测AD的中至高Braak评分的个体的罕见获得病例来量化MTL和额叶皮质内的LC细胞损失和纤维密度;这些病例是一种称为临床前AD（PCAD）的“MCI前”状态的组织等价物。LC光纤损耗是否直接影响MTL目标场中NFT的形成尚不清楚。 我们实验室的初步研究表明，用化合物DSP 4化学损伤LC增加了3xTg-AD小鼠海马CA 1神经元中的NFT病理，提供了LC变性传播NFT病理的新机制证据。 为了探索这种机制，我们使用定制的微阵列来分析从对照和DSP 4处理的3xTg-AD小鼠显微解剖的CA 1神经元中的基因表达差异。 定量分析显示，在DSP 4处理的小鼠中去甲肾上腺素能去传入导致CA 1神经元中的转录因子核呼吸因子1（NRF 1）显著下调80%。 此外，途径分析揭示了一个惊人的模式，其中几个NRF 1转录靶点也被下调，包括调节钙介导的神经元兴奋性的转录物的功能类别（例如， GluR 2 AMPA受体）和线粒体生物发生（例如，细胞色素氧化酶V）。 随后的初步研究表明，NRF 1的表达是严格调节NE和NRF 1选择性减少在海马相比，在aMCI受试者的额叶皮层，跟踪模式的LC deafferentation。因此，我们假设LC投射系统变性通过破坏NRF 1介导的钙离子和线粒体稳态而增强PCAD期间MTL神经元的NFT病理。为了更好地了解NE耗竭对AD临床前过程中MTL神经元变性的影响，我们将联合收割机结合3xTg-AD小鼠的体内操作与探索性微阵列和CA 1神经元的通路分析。 总而言之，这项建议将促进我们的理解的基本机制，潜在的多系统传入LC-MTL记忆电路内，从而在新的信息，疾病的病因和新的目标，及时诊断和治疗方法。