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

• 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
• 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' 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

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

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

聚焦超声与抗 pGlu3 Aβ 通过招募外周免疫细胞增强阿尔茨海默病样小鼠的功效。

• 发表时间: 2021
• 作者: Sun, Tao;Shi, Qiaoqiao;Zhang, Yongzhi;Power, Chanikarn;Hoesch, Camilla;Antonelli, Shawna;Schroeder, Maren K;Caldarone, Barbara J;Taudte, Nadine;Schenk, Mathias;Hettmann, Thore;Schilling, Stephan;McDannold, Nathan J;Lemere, Cynthia A
• 通讯作者: Lemere, Cynthia A

Combination of the Glutaminyl Cyclase Inhibitor PQ912 (Varoglutamstat) and the Murine Monoclonal Antibody PBD-C06 (m6) Shows Additive Effects on Brain Aβ Pathology in Transgenic Mice.

谷氨酰胺环化酶抑制剂 PQ912 (Varoglutamstat) 和鼠单克隆抗体 PBD-C06 (m6) 的组合显示对转基因小鼠脑 Aβ 病理学的附加作用。

• 发表时间: 2021-10-30
• 影响因子: 5.6
• 作者: Hoffmann, Torsten;Rahfeld, Jens;Schenk, Mathias;Ponath, Falk;Makioka, Koki;Hutter;Lues, Inge;Lemere, Cynthia A;Schilling, Stephan
• 通讯作者: Schilling, Stephan

Immunotherapy targeting pyroglutamate-3 Aβ: prospects and challenges.

针对焦谷氨酸 3 Aβ 的免疫疗法：前景与挑战。

• 发表时间: 2016-06-30
• 影响因子: 15.1
• 作者: Cynis, Holger;Frost, Jeffrey L;Crehan, Helen;Lemere, Cynthia A
• 通讯作者: Lemere, Cynthia A

In Vivo Detection of Age- and Disease-Related Increases in Neuroinflammation by 18F-GE180 TSPO MicroPET Imaging in Wild-Type and Alzheimer's Transgenic Mice.

通过 18F-GE180 TSPO MicroPET 成像在野生型和阿尔茨海默病转基因小鼠体内检测与年龄和疾病相关的神经炎症增加。

• 发表时间: 2015-11-25
• 作者: Liu, Bin;Le, Kevin X;Park, Mi;Wang, Shuyan;Belanger, Anthony P;Dubey, Shipra;Frost, Jeffrey L;Holton, Peter;Reiser, Vladimir;Jones, Paul A;Trigg, William;Di Carli, Marcelo F;Lemere, Cynthia A
• 通讯作者: Lemere, Cynthia A

Age-related epigenetic changes in hippocampal subregions of four animal models of Alzheimer's disease.

四种阿尔茨海默病动物模型海马亚区与年龄相关的表观遗传变化。

• 发表时间: 2018
• 作者: Lardenoije, Roy;van den Hove, Daniël L A;Havermans, Monique;van Casteren, Anne;Le, Kevin X;Palmour, Roberta;Lemere, Cynthia A;Rutten, Bart P F
• 通讯作者: Rutten, Bart P F