A new biomarker for frontotemporal lobar degeneration with TDP-43 proteinopathy and Alzheimer's disease

额颞叶变性与 TDP-43 蛋白病和阿尔茨海默病的新生物标志物

基本信息

批准号：
10575426
负责人：
Qinwen Mao
金额：
$ 26.03万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10575426
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease patient Amino Acid Sequence Amyloid beta-Protein Antibodies Area Binding Biological Markers Blood Brain Brain region C-terminal C9ORF72 Cerebrospinal Fluid Classification Clinical Complex Cytoplasm DNA Sequence Alteration Dementia Deposition Diagnosis Disease Exclusion Foundations Frontotemporal Dementia Frontotemporal Lobar Degenerations Funding Future Goals Heterogeneity Human Immunohistochemistry Knowledge Length Link Molecular Molecular Conformation Monoclonal Antibodies Motor Neuron Disease Nerve Degeneration Pathologic Pathology Patients Phenotype Phosphorylation Pilot Projects Primary Progressive Aphasia Proteomics Public Health Reporting Role Symptoms Syndrome Testing Uncertainty behavioral variant frontotemporal dementia clinical phenotype density drug discovery effective therapy hippocampal sclerosis improved meetings neuron loss neuropathology novel protein TDP-43 screening tandem mass spectrometry tau Proteins therapeutic target

项目摘要

Summary The public health impact of TDP-43 (TAR DNA binding protein of 43 kDa) proteinopathy is estimated to be on the same order of magnitude as that of Alzheimer’s disease (AD). TDP-43 was first associated with frontotemporal lobar degeneration (FTLD), the second most common cause of dementia in patients under 65. TDP-43 was later shown to be present in up to 60% of brains with AD, the most common cause of dementia. TDP-43 pathology is heterogeneous in FTLD-TDP and is associated with multiple dementia syndromes, which complicates FTLD-TDP diagnosis in living patients. These patients, who present with a wide range of associated clinical symptoms, are underserved, as their complex clinicopathologic heterogeneity leads to uncertainty surrounding their diagnosis. A major hurdle in elucidating the clinicopathologic relationships between dementia syndromes and specific markers of FTLD-TDP is the heterogeneous molecular species of the TDP-43 inclusions. More specifically, some TDP-43 species are pathologic, while some are not. Similarly, TDP-43 pathology in AD is heterogeneous, and the AD TDP types’ associations with the different molecular species of TDP-43 and neurodegeneration are unknown. Thus, producing an antibody that is specific for the pathologic TDP-43 species will be crucial for elucidating the clinicopathologic relationship in FTLD-TDP and AD. After screening over 5,000 monoclonal antibody (MAb) clones in our lab, we have successfully produced the novel, home-made MAb #9, which is specific for the pathologic TDP-43 species. This antibody can strongly recognize a 35 kDa TDP-43 species rarely reported in humans and can reveal additional dense TDP-43 inclusions in brain areas showing neurodegeneration. The goals of this study are to elucidate this novel, MAb #9-recognized pathologic TDP-43 species and its association with TDP-43 pathology and neurodegeneration in FTLD-TDP and AD. We hypothesize that MAb #9 binds the previously undescribed TDP-43 species present in unique inclusions that localize to brain regions with local neurodegeneration. We will test this hypothesis via three aims. In Aim 1, we will elucidate the amino acid sequence of this novel MAb#9-detected TDP-43 species using tandem mass spectrometry-based proteomic analysis. In Aims 2 and 3, we will determine the relationships between MAb #9- positive inclusions, pathology types, and local neurodegeneration in FTLD-TDP and AD using immunohistochemical and neuropathological approaches. Findings from this study will significantly improve our understanding of a novel toxic TDP-43 species and its association with pathology and neurodegeneration. The findings will be a key step toward developing a biomarker that can predict the presence of TDP-43 in living FTLD and AD patients. Given that TDP-43 is a potential therapeutic target in treating FTLD and now AD, the knowledge will likely also have a significant impact on future therapies for both diseases.

概括 TDP-43（43 kDa 的 TAR DNA 结合蛋白）蛋白病对公共健康的影响估计为与最初与阿尔茨海默病 (AD) 相关的 TDP-43 处于同一数量级。额颞叶变性 (FTLD)，是 65 岁以下患者痴呆症的第二常见原因。后来发现 TDP-43 存在于高达 60% 的 AD 患者大脑中，AD 是痴呆症的最常见原因。 FTLD-TDP 中的 TDP-43 病理学具有异质性，并且与多种痴呆综合征相关，其中这些患者存在多种相关症状，这使得 FTLD-TDP 诊断变得复杂。临床症状得不到充分服务，因为其复杂的临床病理异质性导致不确定性围绕他们的诊断的一个主要障碍是阐明痴呆症之间的临床病理关系。 FTLD-TDP 的综合征和特异性标志物是 TDP-43 包涵体的异质分子种类。更具体地说，一些 TDP-43 物种是病理性的，而另一些则不是，类似地，AD 中的 TDP-43 病理性。是异质的，AD TDP 类型与 TDP-43 和 TDP-43 不同分子种类的关联神经变性是未知的，因此产生了对病理性 TDP-43 物种具有特异性的抗体。经过超过 5,000 次筛查后，这对于阐明 FTLD-TDP 和 AD 的临床病理关系至关重要。在我们的实验室进行单克隆抗体 (MAb) 克隆，我们成功生产了新型自制 MAb #9，该抗体对病理性 TDP-43 物种具有特异性，可以强烈识别 35 kDa TDP-43。人类中很少报道的物种，可以揭示大脑区域中额外的致密 TDP-43 内含物本研究的目的是阐明这种新型 MAb #9 公认的病理性 TDP-43。物种及其与 FTLD-TDP 和 AD 中 TDP-43 病理学和神经变性的关系。 MAb #9 结合先前未描述的 TDP-43 物质，该物质存在于独特的内含物中在目标 1 中，我们将通过三个目标来检验这一假设。将使用串联质谱阐明这种新型 MAb#9 检测到的 TDP-43 物种的氨基酸序列在目标 2 和 3 中，我们将确定 MAb #9- 之间的关系。使用 FTLD-TDP 和 AD 中的阳性包涵体、病理类型和局部神经变性这项研究的结果将显着改善我们的免疫组织化学和神经病理学方法。了解一种新型有毒 TDP-43 物种及其与病理学和神经变性的关系。研究结果将是开发可预测活体 FTLD 中 TDP-43 存在的生物标志物的关键一步鉴于 TDP-43 是治疗 FTLD 和现在 AD 的潜在治疗靶点，这一知识已得到证实。也可能对这两种疾病的未来治疗产生重大影响。