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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/摘要鉴于最近FDA批准了一种基于抗体的药物，该药物可以去除淀粉样蛋白斑块，通过正电子发射断层扫描靶向淀粉样蛋白（PET-淀粉样蛋白）（aducanamab 1），FDA批准了精确性-AD血液检测2，以及提交的lecanemab和donanemab加速批准申请- 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β（Aβ）周转。该提案的总体目标是定量描述斑块内Aβ周转率，体内，在阿尔茨海默病（AD）的各个阶段的人脑组织中，使用稳定同位素标记动力学（丝绸）。通过PET 3 -5测量，基于多种抗体的药物几乎完全去除斑块，与认知能力下降率的降低一起，支持淀粉样蛋白病理学作为关键驱动因素的作用 AD发病机制然而，治疗的持续时间和可能的停止部分取决于是否淀粉样蛋白斑块继续生长和翻转。其他药物（如BACE抑制剂）可以阻止淀粉样斑块生长，菌斑负荷逆转最小（PET约4%/年），表明存在一些自然的缓慢生长。淀粉样斑块的周转。因此，抗淀粉样蛋白治疗的药物试验和临床应用必须基于天然牙菌斑生长的精确模型。最近，实现了人淀粉样蛋白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，以更好地表征蛋白质，脑实质内的肽动力学。具体来说，贝特曼实验室使用纳米级二次离子质谱（NanoSIMS）与SILK偶联，以直接对蛋白质沉积的分布和速率进行成像在来自3名患有AD 6的人类患者的死后组织中的纳米水平的斑块中。然而，NanoSIMS 成像不能确定哪些分子含有检测到的同位素。相比之下，基质辅助激光解吸/电离（MALDI）质谱成像（MALDI-IMS）允许化学特异性Aβ 在AD小鼠模型和死后脑中的病理结构的肽成像，由汉里德实验室7 -10。因此，该小组最近展示了MALDI与SILK的组合以跟踪斑块形成动力学10. 使用来自人类患者的死后组织，这些患者先前在生命期间通过口服摄入15 N- 标记的螺旋藻，我们将通过MALDI-IMS表征具有AD病理学谱的脑中的Aβ周转。这些测量结果将为AD相关蛋白动力学的房室模型提供信息，斑块的微观结构，并延伸到整个身体，一个特别重要的模型，临床批准的诊断生物标志物2、疾病修饰疗法3 -5的曙光时代，以及对于AD的早期迹象的精确理解。

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

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

DOI：
10.1111/jnc.15694
发表时间：
2022-11
期刊：
Journal of neurochemistry
影响因子：
4.7
作者：
通讯作者：

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

Lipid imaging of Alzheimer's disease pathology.

阿尔茨海默病病理学的脂质成像。