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Pyroglutamate Amyloid-beta as an Immunotherapeutic Target for Alzheimer's Disease

焦谷氨酸淀粉样蛋白-β作为阿尔茨海默病的免疫治疗靶点

基本信息

批准号：
8897932
负责人：
CYNTHIA A LEMERE
金额：
$ 33.81万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8897932
关键词：
Acute Affinity Age Age-Months Aging Alzheimer&apos s Disease Amino Acids Amyloid Amyloid Proteins Amyloid beta-Protein Amyloid deposition Animal Model Antibodies Behavioral Bilateral Binding Biochemical Blood Vessels Brain Canis familiaris Carotid Artery Ulcerating Plaque Cerebrum Charge Cognitive Cognitive deficits Collaborations Cyclization Data Deposition Disease Progression Enzyme-Linked Immunosorbent Assay Enzymes Excision Female Flow Cytometry Germany Glutamic Acid Goals Human Hybridomas Image Cytometry Immune response Immunotherapeutic agent Immunotherapy Impaired cognition In Vitro Inflammation Injection of therapeutic agent Intraperitoneal Injections Label Learning Left Length Life Measures Memory Microglia Monoclonal Antibodies Mus N-terminal Neonatal Nerve Degeneration Neurodegenerative Disorders Outcome Measure Passive Immunization Pathogenesis Peptide antibodies Peptides Phagocytosis Play Prevention Proteins Pyroglutamate Reagent Reporting Resistance Role Seeds Staging Technical Expertise Testing Therapeutic Tissues Transgenic Mice Walkers Water aged cellular imaging cytokine experience extracellular glutaminyl-peptide cyclotransferase improved in vivo male mouse model neurotoxic nonhuman primate pathological aging peptide A prevent response synthetic peptide therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): N-terminally-truncated and modified amyloid-beta (A�) peptides are abundant in cerebral amyloid deposits in Alzheimer's disease (AD). Pyroglutamate A� is generated upon N-terminal truncation of A� followed by cyclization by glutaminyl cyclase to convert glutamic acid at residues 3 and 11 to pyroglutamate (A�pE3 and A�pE11). Both forms aggregate quickly, resist degradation, and are neurotoxic. It is unclear if either is present in initial A� deposition in plaques and blood vessels (i.e., acting as a seed for further deposition) or if they are modified later. However, Alzheimer's disease progression appears to correlate with the presence of A� pE peptide aggregates in brain. We hypothesize that pyroglutamate A� acts as a seed for A� deposition and accelerates inflammation, neurodegeneration and cognitive decline; therefore, targeted removal of this toxic species by immunotherapy will reduce A� deposition, inflammation and neuritic dystrophy, and protect against cognitive impairment without disturbing non-pathogenic A�. We propose 4 Specific Aims. Aim 1: We will determine if intrahippocampal or intraperitoneal injections of A�pE-containing mouse brain extracts enhance A� deposition, inflammation, neurodegeneration and cognitive decline in APP/PS1dE9 transgenic mice with aging in vivo. Aim 2: We will determine if early removal of pyroGlu A� prevents general A� plaque deposition and neuritic changes, and protects against cognitive decline by passively immunizing (i.p.) male APP/PS1dE9 tg mice with an anti-A�N3pE mAb (07/1), an anti-A�pE11 mAb, a general A� mAb (3A1), or PBS weekly from 4-12 mo of age, starting prior to plaque onset. Outcome measures: behavioral, biochemical, and neuropathological analyses. Aim 3: We will determine if removal of pyroGlu A� in late stage AD reduces total A� and neurodegeneration and improves cognitive deficits by passively immunizing (i.p.) female APP/PS1dE9 tg mice weekly from 12-16 mo of age, starting well after plaque onset. Antibodies and outcome measures are the same as in Aim 2. Aim 4: We will examine the immune response of microglia to pyroGlu A� mAbs in acute in vivo studies and in primary microglial cultures in vitro. Our collaborators at Probiodrug AG (Germany) will kindly provide us with 2 high-affinity, highly selective pyroGlu A� mAbs (anti- A� pE3 and anti-A�pE11), synthetic A�pE peptides, and brain extracts from their transgenic mouse models that accumulate pyroGlu-3 A� peptides. Our collaborators at the CND have generously provided the 3A1 general A� mAb hybridoma as a control. Importantly, my lab initiated this collaboration and has many years of experience investigating pyroGlu A� deposition, inflammation, and A� immunotherapy. The overall goal of our study is to determine whether pyroglutamate A� proteins (A�pE3 and A�pE11) are therapeutic targets for Alzheimer's disease and, whether clearance by immunotherapy specific for either pyroGlu A� species would be efficacious to prevent and/or treat AD.

描述（由申请人提供）：N-末端截短和修饰的淀粉样β（A β）肽在阿尔茨海默病（AD）的大脑淀粉样沉积物中丰富。焦谷氨酸A β是在A β的N-末端截短后产生的，随后通过N-氨基环化酶环化，将残基3和11处的谷氨酸转化为焦谷氨酸（A β pE 3和A β pE 11）。这两种形式都能迅速聚集，抵抗降解，并具有神经毒性。目前还不清楚是否存在于斑块和血管中的初始A β沉积中（即，作为种子，进一步沉积）或者如果它们稍后被修改。然而，阿尔茨海默病的进展似乎与大脑中A β pE肽聚集体的存在相关。我们假设焦谷氨酸A β作为A β沉积的种子，加速炎症，神经退行性变和认知能力下降;因此，通过免疫疗法有针对性地清除这种有毒物质将减少A β沉积，炎症和神经炎性营养不良，并在不干扰非致病性A β的情况下防止认知障碍。我们提出了四个具体目标。目标1：我们将确定海马内或腹膜内注射含有A β pE的小鼠脑提取物是否会增强APP/PS1 dE 9转基因小鼠体内衰老的A β沉积、炎症、神经变性和认知能力下降。目标二：我们将确定早期去除pyroGlu A β是否可以防止一般A β斑块沉积和神经炎变化，并通过被动免疫（i. p.）从4-12月龄开始，在斑块开始前，每周用抗A β N3 pE mAb（07/1）、抗A β pE 11 mAb、一般A β mAb（3A 1）或PBS处理雄性APP/PS1 dE 9 tg小鼠。结果测量：行为，生化和神经病理学分析。目标3：我们将确定在晚期AD中去除pyroGlu A β是否会减少总A β和神经变性，并通过被动免疫（i. p.）雌性APP/PS1 dE 9 tg小鼠，从12-16月龄开始，每周一次，在斑块发作后开始。抗体和结局指标与目标2相同。目的4：我们将在急性体内研究和体外原代小胶质细胞培养中检测小胶质细胞对pyroGlu A单克隆抗体的免疫应答。我们在Probiodrug AG（德国）的合作者将友好地为我们提供2种高亲和力、高选择性的pyroGlu A β mAb（抗A β pE 3和抗A β pE 11）、合成A β pE肽以及从积累pyroGlu-3 A β肽的转基因小鼠模型中提取的脑提取物。我们在CND的合作者慷慨地提供了3A 1通用A？mAb杂交瘤作为对照。重要的是，我的实验室发起了这项合作，并有多年的研究pyroGlu A沉积，炎症和A免疫疗法的经验。我们研究的总体目标是确定焦谷氨酸A β蛋白（A β pE 3和A β pE 11）是否是阿尔茨海默病的治疗靶点，以及通过对任一种pyroGlu A β物种特异性的免疫疗法清除是否有效预防和/或治疗AD。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The developmental stake hypothesis and changing perceptions of intergenerational relations, 1971-1985.

发展利害关系假设和代际关系观念的变化，1971-1985。

DOI：
10.1093/geront/37.3.394
发表时间：
1997
期刊：
The Gerontologist
影响因子：
0
作者：
Lynott,PP;Roberts,RE
通讯作者：
Roberts,RE

Focused ultrasound with anti-pGlu3 Aβ enhances efficacy in Alzheimer's disease-like mice via recruitment of peripheral immune cells.

DOI：
10.1016/j.jconrel.2021.06.037
发表时间：
2021-08-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
0
作者：
Sun T;Shi Q;Zhang Y;Power C;Hoesch C;Antonelli S;Schroeder MK;Caldarone BJ;Taudte N;Schenk M;Hettmann T;Schilling S;McDannold NJ;Lemere CA
通讯作者：
Lemere CA

DOI：
10.1016/j.mcn.2017.11.002
发表时间：
2018-01
期刊：
Molecular and cellular neurosciences
影响因子：
0
作者：
Lardenoije R;van den Hove DLA;Havermans M;van Casteren A;Le KX;Palmour R;Lemere CA;Rutten BPF
通讯作者：
Rutten BPF

Immunotherapy targeting pyroglutamate-3 Aβ: prospects and challenges.