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）：在阿尔茨海默氏病（AD）的大脑淀粉样蛋白沉积物中，N 端截短和修饰的淀粉样蛋白-β (A�) 肽在 A� 的 N 端截短后生成焦谷氨酸 A�。通过谷氨酰胺酰环化酶环化，将残基 3 和 11 处的谷氨酸转化为焦谷氨酸（A�pE3 和 A�pE11）。两种形式都可以快速聚集，抵抗降解，并且具有神经毒性。尚不清楚是否存在于斑块和血管中的初始 A� 沉积中（即，充当 A� 的种子）。然而，阿尔茨海默病的进展似乎与大脑中 A� pE 肽聚集体的存在有关。我们认为焦谷氨酸 A� 充当 A� 沉积的种子，并加速炎症和神经退行性变。和认知能力下降；因此，通过免疫疗法有针对性地去除这种有毒物质将减少 A� 沉积、炎症和神经炎性营养不良，并在不干扰非致病性 A� 的情况下预防认知障碍。目标 1：我们将确定海马内或腹膜内注射含有 A�pE 的小鼠大脑提取物是否会增强 APP/PS1dE9 转基因小鼠体内衰老的 A�沉积、炎症、神经变性和认知能力下降。去除pyroGlu A的一般A斑沉积和神经炎变化，并通过被动免疫（腹腔注射）男性来防止认知能力下降APP/PS1dE9 tg 小鼠从 4-12 月龄开始，每周使用抗 A�N3pE mAb (07/1)、抗 A�pE11 mAb、通用 A� mAb (3A1) 或 PBS，在结果测量：行为、生化和神经病理学分析目标 3：我们将确定 AD 晚期去除 PyroGlu A� 是否会减少总 A� 和从斑块出现后开始，每周对 12-16 个月龄的雌性 APP/PS1dE9 tg 小鼠进行被动免疫（腹膜内注射），以抑制神经退行性疾病并改善认知缺陷。抗体和结果测量与目标 2 中的相同。目标 4：我们。我们在 Probiodrug AG 的合作者将在急性体内研究和体外原代小胶质细胞培养中检查小胶质细胞对pyroGlu A� mAb 的免疫反应。（德国）将向我们提供 2 种高亲和力、高选择性的pyroGlu A� 单克隆抗体（抗 A� pE3 和抗 A� pE11）、合成 A�pE 肽以及来自积累了pyroGlu 的转基因小鼠模型的脑提取物-3 A� 肽。 CND 的合作者慷慨地提供了 3A1 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。并拥有多年研究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�蛋白（A�pE3和A�pE11）是否是阿尔茨海默病的治疗靶点。通过针对任一pyroGlu A�物种的特异性免疫疗法进行清除是否可以有效预防和/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.