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.

7.项目总结 在65岁以上的患者中，ADRD痴呆占所有痴呆的25%，而且有很强的 由淀粉样蛋白β(Aβ)、tau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和70%以上的PDD中或重度 DLB患者伴有AD相关病理，因此这些患者经历了更多的异质性， 速度较快，临床表型严重。认知障碍与突触丢失密切相关 突触功能障碍是治疗的关键靶点 最终由多种有毒寡聚体(αSyn，Aβ和tau)造成的突触丢失，开始于它们与PrPC的结合， 必须被阻止。我们的结果表明，口服小肽CCR5拮抗剂RAP-103可以有效地预防这两种情况 α、Syn和β通过阻断PrPc的激活而在啮齿动物和人类神经元中介导的脊椎和突触丢失 破坏微管、脊椎结构和突触功能。RAP-103保护的啮齿动物和人神经元 α突触和β诱导的缺失，以及表达人α突触的动物的初步研究 模型行6116，预防认知缺陷。通过与神经元CCR5结合，RAP-103发挥变构作用 抑制膜结合的PrPc/NOX复合体激活以阻断多个有毒低聚物的停止， 可能是相反的，包括LBD在内的ADRD的突触丢失和认知能力下降。利用Tg4510型混合α- 我们将对RAP-103对突触的保护作用进行明确的体内研究 脑组织化学分析与ADRDS相关的密度和疾病生物标志物。我们会在活体内比较 [18F]SynVesT-1活体动物SV2APET显像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6至7个月期间口服RAP-103 动物会经历突触丢失。我们将确定RAP-103对脑突触密度标记物的影响 用定量方法检测突触囊泡突触素1在大脑皮层和海马区的表达 蛋白质和SVA2，PET成像示踪剂的靶点，并与NeuN在Pre-Pre中标准化为总神经元密度 确定感兴趣的区域。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、寡聚体Tau、pThr231Tau、多聚体总α同步和pSer129 αSyn.AIMS的成功完成将支持RAP-103用于突触保护的进一步开发 SV2APET显像与[18F]SynVesT-1联合应用对脑出血的影响及建议 ADRD中的突触发生，然后可以与用于人类的生物标记物和认知益处相关 测试。