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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.

项目摘要/摘要鉴于FDA最近批准了一种基于抗体的药物，可以根据测量去除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)(Aducanamab1)，FDA批准 Preciality-AD血液检测2，并提交了加速批准lecanemab和donanemab的申请- PET-淀粉样蛋白成像3-5显示基于抗体的药物也能减少斑块--迫切需要更好地了解斑块中的天然淀粉样β蛋白(Aβ)周转。这项建议的总体目标是定量表征斑块内Aβ周转率用稳定同位素标记动力学研究阿尔茨海默病(AD)不同阶段人脑组织中的活体 (丝绸)。根据PET3-5的测量，多种基于抗体的药物几乎完全消除了斑块再加上认知衰退速度的降低，支持淀粉样蛋白病理作为关键驱动因素的作用阿尔茨海默病的发病机制。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斑块继续生长并翻转。其他药物(如BACE抑制剂)可以阻止淀粉样斑块生长和斑块负荷的最小逆转(~4%/年的PET)，表明有一些自然的缓慢淀粉样斑块的周转。因此，抗淀粉样蛋白疗法的药物试验和临床应用必须基于天然斑块生长的准确模型。最近，对人淀粉样斑块体内代谢生长的显微分辨已经实现。通过将丝绸与基于质谱学的成像方法(“Isilk”)相结合，以更好地表征蛋白质和脑实质内的多肽动力学。具体地说，贝特曼实验室使用了纳米级的二次离子与蚕丝偶联的质谱仪(NanoSIMS)直接成像蛋白质沉积的分布和速度在3名AD6患者的死后组织中纳米级的斑块中。然而，NanoSIMS 成像无法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)基于质谱学的成像(MALDI-IMS)允许化学特异性的Aβ AD小鼠模型和死后脑病理结构的多肽成像研究因此，该小组最近展示了MALDI与丝绸的结合跟踪斑块形成的动力学。使用生前口服15N-1标记的人类患者的死后组织被标记为螺旋藻，我们将用MALDI-IMS表征具有AD病理谱的大脑中的Aβ周转。这些测量将提供AD相关蛋白质动力学的隔室模型，从斑块的微观结构并延伸到整个身体，这是一种特别重要的模型临床批准的诊断生物标记物2、疾病修正疗法3-5的曙光时代，以及迫切需要以准确了解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

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。