PET Imaging to Evaluate a Novel Chemokine Antagonist to Protect Synapses in ADRD

PET 成像评估新型趋化因子拮抗剂保护 ADRD 突触

• 批准号: 10818903
• 负责人: Michael R Ruff
• 金额: $ 32.48万
• 依托单位: CREATIVE BIO-PEPTIDES, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818903
• 关键词: Age; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Animals; Antibodies; Autopsy; Binding; Biological Markers; Brain; Brain Injuries; CCR5 gene; Cognition; Cognitive deficits; Complex; Creativeness; Dementia; Development; Disease; Dose; Etiology; Euthanasia; Frontotemporal Dementia; Functional disorder; Harvest; Hippocampus; Human; Impaired cognition; Lewy Body Dementia; Measures; Mediating; Membrane; Memory Loss; Methods; Microtubules; Modeling; Mus; Mutation; Natural regeneration; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Oral; Pathology; Patients; Peptides; Phase; Pilot Projects; Positron-Emission Tomography; PrP; PrPC Proteins; Presynaptic Terminals; Proteins; Research; Rodent; Structure; Surface; Synapses; Synaptic Vesicles; Synaptophysin; System; Tauopathies; Testing; Tracer; Vertebral column; Work; abeta oligomer; age related; alpha synuclein; antagonist; basal forebrain; brain tissue; cerebral atrophy; chemokine; chemokine receptor; clinical phenotype; cognitive benefits; cognitive function; comorbidity; comparison control; density; experience; frontal lobe; human old age (65+); in vivo; interest; mixed dementia; neuroinflammation; neuron loss; novel; older patient; overexpression; phosphoneuroprotein 14; prevent; protective effect; quantitative imaging; receptor; response; synaptic function; synaptogenesis; synuclein; tau Proteins; tau aggregation; treatment duration

7. Project Summary ADRD dementias account for up to 25% of all dementias in patients older than 65 years and there is strong evidence of co-morbid pathologies caused by (amyloid β (Aβ), tau and α-synuclein (αSyn). The degree of AD- related pathology in Lewy Body Dementias (LBD) is moderate or severe in 50% of PDD and more than 70% of DLB patients have concomitant AD-related pathology so that these patients experience a more heterogeneous, faster, and severe clinical phenotype. Cognitive impairment is closely associated with synapse loss which occurs significantly prior to neuronal loss suggesting that synaptic dysfunction is the key treatment target and that ultimately synapse loss by multiple toxic oligomers (αSyn, Aβ, and tau), that begins with their binding to PrPc, must be stopped. Our results show that RAP-103, a small oral peptide CCR5 antagonist potently prevents both αSyn and Aβ-mediated spine and synapse loss in rodent and human neurons by blocking PrPc activation that disrupts microtubules, spine structure and synapse function. RAP-103 protected rodent and human neuron spines and synapses from αSyn and Aβ-induced loss, and in a pilot study of the human αSyn expressing animal model Line 6116, prevented cognitive deficits. By binding to neuronal CCR5, RAP-103 exerts an allosteric inhibitory effect on membrane bound PrPc/NOX complex activation to block multiple toxic oligomers to stop, possibly reverse, synapse loss and cognitive decline in ADRD including LBD. Utilizing the Tg4510 mixed α- Syn/Tauopathy animal model we will conduct a definitive in vivo study of RAP-103 protective effects on synapse density and disease biomarkers relevant to ADRDs by brain histochemical analysis. We will compare in vivo histochemical analysis of synapse density to live animal SV2A PET imaging with [18F]SynVesT-1 as a quantitative biomarker of synaptogenesis. We will administer RAP-103 by oral dosing from months 6 to 7 when animals experience synapse loss. We will determine RAP-103 effects on markers of brain synapse density in cortex and hippocampus by quantitative methods measuring expression of Synaptophysin 1, a synaptic vesicle protein and SVA2, the target of the PET imaging tracer and normalize to total neuron density with NeuN in pre- identified regions of interest. We will also determine RAP-103 effects on disease biomarkers by measuring the number of neurofibrillary tangles-NFT load, oligomeric Tau, pThr231Tau, Multimeric total αSyn and pSer129 αSyn. Successful completion of the Aims will support further development of RAP-103 for synapse protecting effects and suggest using SV2A PET imaging with [18F]SynVesT-1 as a quantitative biomarker of synaptogenesis in ADRDs, which can then be correlated with biomarkers and cognitive benefits for use in human testing.

七、项目概要 ADRD 痴呆症占 65 岁以上患者所有痴呆症的 25%，并且有很强的相关性。 由β淀粉样蛋白 (Aβ)、tau 蛋白和 α-突触核蛋白 (αSyn) 引起的共病病理的证据。AD- 的程度 路易体痴呆 (LBD) 的相关病理在 50% 的 PDD 中为中度或重度，超过 70% 的 PDD 为中度或重度。 DLB 患者伴有 AD 相关病理，因此这些患者经历了更加异质性、 更快、更严重的临床表型。认知障碍与发生的突触损失密切相关 明显早于神经元损失，表明突触功能障碍是关键的治疗目标，并且 最终，多种有毒寡聚体（αSyn、Aβ 和 tau）导致突触损失，这始于它们与 PrPc 的结合， 必须停止。我们的结果表明，RAP-103（一种小型口服肽 CCR5 拮抗剂）可有效预防这两种情况 αSyn 和 Aβ 通过阻断 PrPc 激活来介导啮齿动物和人类神经元的脊柱和突触损失 破坏微管、脊柱结构和突触功能。 RAP-103保护啮齿动物和人类神经元 αSyn 和 Aβ 诱导的损失中的棘和突触，以及在人类 αSyn 表达动物的初步研究中 Line 6116 型号，可预防认知缺陷。通过与神经元 CCR5 结合，RAP-103 发挥变构作用 对膜结合 PrPc/NOX 复合物激活的抑制作用，阻止多种有毒低聚物的停止， ADRD（包括 LBD）中的突触丧失和认知能力下降可能会逆转。利用 Tg4510 混合 α- Syn/Tauopathy 动物模型，我们将对 RAP-103 对突触的保护作用进行明确的体内研究 通过脑组织化学分析与 ADRD 相关的密度和疾病生物标志物。我们将在体内进行比较 使用 [18F]SynVesT-1 作为活体动物 SV2A PET 成像的突触密度的组织化学分析 突触发生的定量生物标志物。我们将在第 6 至 7 个月期间通过口服给药 RAP-103 动物会经历突触丧失。我们将确定 RAP-103 对大脑突触密度标记物的影响 通过定量方法测量皮质和海马突触泡蛋白 1（一种突触小泡）的表达 蛋白质和 SVA2（PET 成像示踪剂的目标），并使用 NeuN 标准化总神经元密度 确定的感兴趣区域。我们还将通过测量 RAP-103 对疾病生物标志物的影响来确定 神经原纤维缠结的数量 - NFT 负载、寡聚 Tau、pThr231Tau、多聚总 αSyn 和 pSer129 α同步。目标的成功完成将支持 RAP-103 用于突触保护的进一步开发 效应并建议使用 SV2A PET 成像和 [18F]SynVesT-1 作为定量生物标志物 ADRD 中的突触发生，然后可以与人类使用的生物标志物和认知益处相关联 测试。