Human in vivo stable isotope labeling kinetics (iSILK) to quantify brain amyloid plaque kinetics

人体内稳定同位素标记动力学 (iSILK) 用于量化脑淀粉样斑块动力学

基本信息

批准号：
10509111
负责人：
Jorg Hanrieder
金额：
$ 41.1万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10509111
关键词：
Address Aducanumab Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amyloid Amyloid beta-Protein Antibodies Architecture Area Autopsy Basal Ganglia Biochemical Biological Markers Brain Brain Stem Brain region Cerebellum Cerebrospinal Fluid Cerebrum Chemicals Clinic Clinical Clinical Trials Cognitive Coupled Deposition Development Diagnostic Diffuse Disease Evaluation Excision FDA approved Freezing Frequencies Goals Growth Hematological Disease Human Image Immunoprecipitation Impaired cognition Individual Intercellular Fluid Isotope Labeling Isotopes Kinetics Knowledge Label Laboratories Lasers Life Measurement Measures Metabolic Microscopic Midbrain structure Modeling Molecular Molecular Conformation Monitor Morphology N-terminal Neocortex Nitrogen Oral Ingestion Pathogenesis Pathogenicity Pathologic Patients Peptides Pharmaceutical Preparations Phase Plasma Positron-Emission Tomography Protein Isoforms Proteins Pyroglutamate Research Resolution Role Sampling Senile Plaques Slice Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Spectrometry, Mass, Secondary Ion Spirulina preparation Stable Isotope Labeling Stains Structure Time Tissues To specify Withholding Treatment abeta accumulation amyloid pathology amyloid structure antibody detection base beta-site APP cleaving enzyme 1 brain parenchyma brain tissue clinically relevant cohort conformational conversion density diencephalon experimental study fluorescence imaging hospice environment human tissue imaging modality in vivo inhibitor insight mass spectrometric imaging mouse model nanometer nanoscale new therapeutic target novel marker targeted treatment tau Proteins treatment strategy

项目摘要

Project summary / abstract Given the recent FDA approval of an antibody-based drug that can remove amyloid plaques as measured by positron-emission tomography targeting amyloid (PET-amyloid) (aducanamab1), the FDA approval of the Precivity-AD blood test2, and applications submitted for accelerated approval of lecanemab and donanemab – antibody-based drugs also shown to reduce plaque by PET-amyloid imaging3–5 – there is an urgent need to better understand the natural amyloid-beta (Aβ) turnover in plaques. The overall goal of this proposal is to quantitatively characterize the rate of Aβ turnover within plaques in vivo, in human brain tissue at various stages of Alzheimer's disease (AD) using stable isotope labeling kinetics (SILK). That multiple antibody-based drugs nearly completely remove plaques as measured by PET3–5, taken together with a reduction in the rate of cognitive decline, supports a role for amyloid pathology as critical driver of AD pathogenesis. However, the duration and possible cessation of treatment is partly dependent on whether amyloid plaques continue to grow and turn over. Other drugs (e.g. BACE inhibitors) can stop amyloid plaque growth with minimal reversal of plaque load (~4%/year by PET), suggesting that there is some natural slow turnover of amyloid plaques. Drug trials and clinical use of anti-amyloid therapies thus must be based on accurate models of natural plaque growth. Very recently, microscopic resolution of in vivo metabolic growth of human amyloid plaques was achieved by combining SILK with mass spectrometric-based imaging methods (“iSILK”) to better characterize protein and peptide kinetics within brain parenchyma. Specifically, the Bateman laboratory used nanoscale secondary ion mass spectrometry (NanoSIMS) coupled to SILK to directly image the distribution and rate of protein deposition in plaques at the nanometer level in postmortem tissue from 3 human patients with AD6. However, NanoSIMS imaging fails to specify which molecules contain the detected isotopes. In contrast, matrix-assisted laser desorption / ionization (MALDI) mass spectrometry-based imaging (MALDI-IMS) allows chemically-specific Aβ peptide imaging of pathologic structures in AD mouse models and postmortem brain, which has been pioneered by the Hanrieder lab7–10. Consequently, the group very recently demonstrated MALDI in combination with SILK to follow plaque formation dynamics10. Using postmortem tissue from human patients previously labeled during life by oral ingestion of 15N- labeled spirulina, we will characterize Aβ turnover by MALDI-IMS in brains with a spectrum of AD pathology. These measurements will inform a compartmental model of AD-related protein kinetics starting at the microscopic structure of the plaque and extending throughout the body, a particularly important model in the dawning era of clinically-approved diagnostic biomarkers2, disease-modifying therapies3–5, and the critical need for a precise understanding of the earliest signs of AD.

项目概要/摘要鉴于 FDA 最近批准了一种基于抗体的药物，可以去除测量的淀粉样斑块通过正电子发射断层扫描靶向淀粉样蛋白 (PET-淀粉样蛋白) (aducanab1)，FDA 批准了 Precivity-AD 血液检测2，以及为加速批准 Lecanemab 和 donanemab 提交的申请 – PET-淀粉样蛋白成像也显示基于抗体的药物可以减少斑块3-5——迫切需要更好地了解斑块中的天然淀粉样蛋白 (Aβ) 周转情况。该提案的总体目标是定量表征斑块内 Aβ 周转率使用稳定同位素标记动力学在阿尔茨海默病 (AD) 各个阶段的人脑组织中进行体内研究 (SILK) 通过 PET3-5 测量，多种基于抗体的药物几乎完全去除了斑块。加上认知能力下降速度的降低，支持淀粉样蛋白病理作为关键驱动因素的作用然而，治疗的持续时间和可能的停止部分取决于是否淀粉样斑块继续生长和更新其他药物（例如 BACE 抑制剂）可以阻止淀粉样斑块。牙菌斑负荷逆转最小（PET 测定约 4%/年），表明存在一些自然缓慢的生长因此，药物试验和抗淀粉样蛋白疗法的临床使用必须基于淀粉样蛋白斑的周转。自然斑块生长的准确模型。最近，实现了人类淀粉样斑块体内代谢生长的显微分辨率通过将 SILK 与基于质谱的成像方法（“iSILK”）相结合，更好地表征蛋白质和具体来说，贝特曼实验室使用了纳米级二次离子。质谱 (NanoSIMS) 与 SILK 耦合，可直接对蛋白质沉积的分布和速率进行成像然而，NanoSIMS 发现了 3 名 AD6 患者死后组织中的纳米级斑块。相比之下，基质辅助激光无法确定哪些分子含有检测到的同位素。基于解吸/电离 (MALDI) 质谱成像 (MALDI-IMS) 可实现化学特异性 Aβ AD小鼠模型和死后大脑病理结构的肽成像，这是首创的经 Hanrieder 实验室 7-10 检查，该小组最近展示了 MALDI 与 SILK 的结合。跟踪斑块形成动态10。使用以前通过口服摄入 15N- 来标记的人类患者的死后组织标记为螺旋藻，我们将通过 MALDI-IMS 表征具有一系列 AD 病理学的大脑中的 Aβ 转换。这些测量结果将为 AD 相关蛋白质动力学的区室模型提供信息，该模型从斑块的微观结构并延伸到全身，这是一个特别重要的模型临床批准的诊断生物标志物2、疾病缓解疗法3-5的黎明时代，以及迫切的需求准确了解 AD 的最早迹象。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Correlative Chemical Imaging and Spatial Chemometrics Delineate Alzheimer Plaque Heterogeneity at High Spatial Resolution.

DOI：
10.1021/jacsau.2c00492
发表时间：
2023-03-27
期刊：
JACS AU
影响因子：
8
作者：
Wehrli, Patrick M;Ge, Junyue;Michno, Wojciech;Koutarapu, Srinivas;Dreos, Ambra;Jha, Durga;Zetterberg, Henrik;Blennow, Kaj;Hanrieder, Jorg
通讯作者：
Hanrieder, Jorg

Correlative Chemical Imaging Identifies Amyloid Peptide Signatures of Neuritic Plaques and Dystrophy in Human Sporadic Alzheimer's Disease.

相关化学成像识别人类散发性阿尔茨海默病神经炎斑块和营养不良的淀粉样肽特征。

DOI：
10.1089/brain.2022.0047
发表时间：
2023
期刊：
Brain connectivity
影响因子：
3.4
作者：
Koutarapu,Srinivas;Ge,Junyue;Jha,Durga;Blennow,Kaj;Zetterberg,Henrik;Lashley,Tammaryn;Michno,Wojciech;Hanrieder,Jörg
通讯作者：
Hanrieder,Jörg

Tetramodal Chemical Imaging Delineates the Lipid-Amyloid Peptide Interplay at Single Plaques in Transgenic Alzheimer's Disease Models.

DOI：
10.1021/acs.analchem.2c05302
发表时间：
2023-03-14
期刊：
ANALYTICAL CHEMISTRY
影响因子：
7.4
作者：
Ge, Junyue;Koutarapu, Srinivas;Jha, Durga;Dulewicz, Maciej;Zetterberg, Henrik;Blennow, Kaj;Hanrieder, Joerg
通讯作者：
Hanrieder, Joerg

Chemical traits of cerebral amyloid angiopathy in familial British-, Danish-, and non-Alzheimer's dementias.