Cellular and Molecular Medial Temporal Lobe Pathology in Elderly PreMCI subjects

老年 PreMCI 受试者的细胞和分子内侧颞叶病理学

基本信息

批准号：
8574411
负责人：
STEPHEN D GINSBERG
金额：
$ 67.29万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8574411
关键词：
Address Alleles Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Antibodies Apolipoprotein E Appearance Atrophic Automobile Driving Biochemical Brain Brodmann&apos s area Brodmann&apos s area 28 Cathepsins Cells Clinical Complex Data Dementia Development Disease Economics Elderly Environment Episodic memory Epitopes Ethers Event Evolution Family Functional disorder GTPase Gene Generations Genes Genotype Goals Health Care Costs Health Policy Hippocampal Formation Hippocampus (Brain)Homeostasis Housing Human Impaired cognition Individual Intervention Investigation Knowledge Label Lesion Literature Medial Mediator of activation protein Memory Microarray Analysis Molecular Molecular Profiling Nerve Degeneration Neurofibrillary Tangles Neuronal Dysfunction Neurons Pathogenesis Pathologic Pathology Pattern Pharmacotherapy Play Polymers Positioning Attribute Post-Translational Protein Processing Process Protein Isoforms Public Health Risk Role Signal Transduction Site Societies Staining method Stains Structure Synapses Temporal Lobe Testing Therapeutic Intervention Tissues Up-Regulation aging population amyloid pathology apolipoprotein E-2 apolipoprotein E-4 base clinical Diagnosis disorder prevention entorhinal cortex feeding genetic risk factor immunoreactivity interest mRNA Expression mild cognitive impairment morphometry neurofibrillary tangle formation neuropathology novel pre-clinical protein metabolism public health relevance rab GTP-Binding Proteins relating to nervous system screening senescence spatiotemporal stellate cell tau Proteins tau phosphorylation

项目摘要

DESCRIPTION (provided by applicant): By 2050 older people at risk for cognitive decline are predicted to reach 13 million and health care costs are borne by individuals, their families, and society at large. The overall goal of the proposed project is determine the earliest cellular and molecular changes underlying the disconnection of the neuronal memory circuit within the medial temporal lobe (MTL), which degenerates in a highly predictable region-to-region pattern beginning prior to the onset of cognitive decline in the elderly. A growing literature implicated endosmal/lysosomal (E-L) dysfunction occur even before the formation of the classic pathologic AD lesion, the neurofibrillary tangle (NFT), composed of polymers of the microtubule-associated protein, tau. NFTs occur first in the transentorhinal cortex (TEC) then spread to the entorhinal cortex (EC) layer II and then to the hippocampal formation (HF) CA1 neurons of the MTL. Our group has shown that E-L rab GTPase genes are dysregulated in HPC CA1 neurons in MCI. Building on these findings, we propose to perform single cell expression profiling combined with site specific tau antibody neuronal labeling to test whether select rab GTPases are differentially regulated early during the evolution of TEC layer III NFTs prior to ether EC or HF prior to cognitive decline. We will examine whether select tau cytoskeletal isoforms and/or rab expression correlate with clinical diagnosis, memory tests specific to the MTL connectome, amyloid and apolipoprotein E genotype in preclinical AD. The project will characterize how pathology alters the neuronal environment at the mRNA expression level and provide new information on the complex mechanism(s) driving the molecular pathogenesis underlying MTL degeneration before clinical onset of dementia. This timely, novel and powerful approach will transform our understanding of the contributions of E-L expression to the vulnerability of MTL neurons in preclinical AD. The project is well positioned to lay the groundwork for a wide range of potential interventions that are truly distinct from approaches currently under investigation. I addition, the novel information gained about role that intraneuronal site-specific tau epitopes, E-L activation and amyloid pathology play in the vulnerability of MTL neurons may provide a panel of targets to better inform CSF tau based screening for dementia onset.

描述（由申请人提供）：到 2050 年，面临认知能力下降风险的老年人预计将达到 1300 万，医疗保健费用将由个人、家庭和整个社会承担。该项目的总体目标是确定内侧颞叶（MTL）内神经元记忆回路断开的最早的细胞和分子变化，该回路在神经元记忆回路发生之前开始以高度可预测的区域到区域模式退化。老年人认知能力下降。越来越多的文献表明，内质/溶酶体 (E-L) 功能障碍甚至在典型的 AD 病理性病变——由微管相关蛋白 tau 的聚合物组成的神经原纤维缠结 (NFT) 形成之前就发生了。 NFT 首先发生在经内嗅皮质 (TEC)，然后扩散到内嗅皮质 (EC) II 层，然后扩散到 MTL 的海马结构 (HF) CA1 神经元。我们的小组已经表明，MCI 中的 HPC CA1 神经元中 E-L rab GTPase 基因失调。基于这些发现，我们建议结合位点特异性 tau 抗体神经元标记进行单细胞表达谱分析，以测试在认知能力下降之前的 TEC III 层 NFT 进化过程中，选定的 rab GTP 酶是否在 TEC III 层 NFT 的进化早期受到差异性调节。我们将检查选定的 tau 细胞骨架亚型和/或 rab 表达是否与临床前 AD 中的临床诊断、MTL 连接组特异性记忆测试、淀粉样蛋白和载脂蛋白 E 基因型相关。该项目将描述病理学如何在 mRNA 表达水平上改变神经元环境，并提供有关在痴呆症临床发病前驱动 MTL 变性的分子发病机制的新信息。这种及时、新颖且强大的方法将改变我们对 E-L 表达对临床前 AD 中 MTL 神经元脆弱性的影响的理解。该项目处于有利地位，可以为广泛的潜在干预措施奠定基础，这些干预措施与目前正在研究的方法真正不同。此外，关于神经元内特定位点 tau 表位、E-L 激活和淀粉样蛋白病理学在 MTL 神经元脆弱性中所起的作用的新信息可能会提供一组目标，以便更好地为基于 CSF tau 的痴呆发作筛查提供信息。