Immunomodulation targeting abnormal conformation and the influence of apoE

针对异常构象的免疫调节及apoE的影响

• 批准号: 10428586
• 负责人: Fernando goni
• 金额: $ 46.39万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10428586
• 关键词: 3xTg-AD mouse; APP-PS1; Active Immunization; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Animal Model; Animals; Antibodies; Antibody Binding Sites; Antibody Response; Apolipoprotein E; Autoimmune; Behavioral; Binding; Binding Sites; Biochemical; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Brain; Cerebral Amyloid Angiopathy; Cerebrovascular system; Characteristics; Clinical Trials; Cognitive; Complication; Elderly; Female; Future; Hemorrhage; Human; Image; Immune Targeting; Immunization; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunotherapy; Injections; Intraperitoneal Injections; Kinetics; Knock-in; Legal patent; Mass Spectrum Analysis; Measures; Mediating; Modeling; Molecular Conformation; Monoclonal Antibodies; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Passive Immunization; Passive Immunotherapy; Pathogenesis; Pathologic; Pathology; Peptoids; Peripheral; Permeability; Proteome; Proteomics; Reporting; Safety; Senile Plaques; Sterility; Structure; Testing; Therapeutic Effect; Toxic effect; Vaccination; Western Blotting; abeta oligomer; amyloid structure; apolipoprotein E-4; autoimmune toxicity; beta pleated sheet; blood-brain barrier penetration; cognitive testing; conformer; extracellular; human tissue; hyperphosphorylated tau; immunological intervention; immunoregulation; innovation; insight; male; misfolded protein; mouse model; nanomolar; neuropathology; novel strategies; oAβ; prion-like; side effect; small molecule; tau Proteins; tau aggregation; vascular abnormality

SUMMARY The neuropathology of AD includes fibrillary amyloid β (Aβ) in plaques, cerebral amyloid angiopathy (CAA), and hyperphosphorylated tau fibrils in neurofibrillary tangles (NFT). However, the most toxic species are Aβ and tau oligomers characterized by generic structural β-sheet secondary structure. These misfolded Aβ and tau conformers are suitable targets for immunological intervention, although numerous clinical trials thus far have failed due to: 1) autoimmune toxicity; 2) lack of specific concomitant targeting of oligomeric Aβ and tau species; and 3) Amyloid Related Imaging Abnormalities (ARIA), particularly among apolipoprotein (apo)E4 carriers, thought to be associated with fibrillar vessel amyloid clearance. To overcome these limitations, we developed innovative antibody combining sites (aβComAb paratopes) that only recognize the dominant β- sheet secondary structure of misfolded proteins, a generic characteristic of all pathologic oligomers found in neurodegenerative diseases. Our preliminary results show that some aβComAb combining sites on either IgM or IgG class can, without side effects, penetrate the BBB of an AD Tg mouse model with pre-existing Aβ and tau pathology, achieve significant cognitive rescue, reduce levels of Aβ and tau pathological oligomers, and in a CAA AD Tg mouse model (TgSwDI) act without ARIA-like toxicity (both models on murine apoE background). In this project, we will test the hypothesis that aβComAbs (IgM or IgG), unlike mAbs directed against Aβ sequences (6E10), can be infused safely and produce modifying therapeutic effects without vascular ARIA-like toxicity in 3xTg and the vascular TgSwDI or APP/PS1dE9 mouse models cross-bred to human apoE2, E3, or E4 backgrounds. Furthermore, we anticipate that the vascular amyloid proteomes of these mice will resemble those that Projects 1 and 2 associate with different apoE backgrounds, treatments, and presence or absence of microhemorrhages. This information is critically needed to elucidate the mechanism associated with ARIA and select aβComAbs paratopes for future clinical trials. The specific aims are to: 1) Produce and characterize IgM and IgG forms of combining sites (AβComAb paratopes) that specifically recognize the β-sheet secondary structures of toxic oligomers. 2) Determine the biochemical and histochemical interaction of the four aβComAbs from Aim 1 with the brain vasculature of peripherally infused TgSwDI mice crossed on KI human ApoE2, E3, and E4 backgrounds. 3) Determine behavioral, histochemical, and biochemical changes after passive immunotherapy with two AβComAb paratopes on an IgM and an IgG selected from Aim 2, in 3xTg, Tg APP/PS1dE9, and TgSwDI mice crossed on KI human ApoE2, E3, and E4 backgrounds.

概括 AD 的神经病理学包括斑块中的纤维状淀粉样蛋白 β (Aβ)、脑淀粉样血管病 (CAA)、 然而，毒性最强的种类是 Aβ。 和 tau 寡聚物的特征是通用结构 β-折叠二级结构。 tau 构象异构体是免疫干预的合适靶标，尽管迄今为止有大量临床试验 失败的原因是：1) 自身免疫毒性；2) 缺乏寡聚 Aβ 和 tau 的特异性联合靶向 3) 淀粉样蛋白相关影像异常 (ARIA)，特别是载脂蛋白 (apo)E4 载体，被认为与纤维血管淀粉样蛋白清除有关，为了克服这些限制，我们。 开发了创新的抗体结合位点（aβComAb 互补位），仅识别占主导地位的 β- 错误折叠蛋白质的片状二级结构，这是所有病理性寡聚物的一般特征 我们的初步结果表明，任一 IgM 上都有一些 aβComAb 结合位点。 或 IgG 类可以无副作用地穿透具有预先存在的 Aβ 和 AD Tg 小鼠模型的 BBB tau 病理学，实现显着的认知救援，降低 Aβ 和 tau 病理寡聚体的水平，并在 CAA AD Tg 小鼠模型 (TgSwDI) 没有 ARIA 样毒性（两种模型均针对小鼠 apoE 在这个项目中，我们将测试 aβComAbs（IgM 或 IgG）的假设，与 mAbs 定向不同。 针对 Aβ 序列 (6E10)，可以安全输注并产生改变治疗效果，无需 3xTg 和血管 TgSwDI 或 APP/PS1dE9 杂交小鼠模型中的血管 ARIA 样毒性 此外，我们预计血管淀粉样蛋白。 这些小鼠的蛋白质组将类似于项目 1 和 2 与不同 apoE 相关的蛋白质组 背景、治疗以及是否存在微出血，这些信息至关重要。 需要阐明与 ARIA 相关的机制并为未来的临床选择 aβComAbs 互补位 试验的具体目标是： 1) 产生并表征 IgM 和 IgG 形式的结合位点（AβComAb 互补位），这些位点特异性地 识别有毒低聚物的 β-折叠二级结构。 2) 确定目标 1 中的四种 aβComAb 与大脑的生化和组织化学相互作用 外周输注 TgSwDI 小鼠的脉管系统在 KI 人 ApoE2、E3 和 E4 背景上交叉。 3) 确定两种被动免疫治疗后的行为、组织化学和生化变化 3xTg、Tg APP/PS1dE9 和 TgSwDI 小鼠中选自 Aim 2 的 IgM 和 IgG 上的 AβComAb 互补位 在 KI 人类 ApoE2、E3 和 E4 背景上进行杂交。