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。项目摘要 ADRD痴呆症占65岁以上患者的所有痴呆症的25％，并且有强大的痴呆症 由淀粉样蛋白β（Aβ），TAU和α-核蛋白（αSyn）引起的合并病理学的证据。 Lewy身体痴呆症（LBD）的相关病理中的50％的PDD中等或重度，超过70％ DLB患者患有与广告相关的病理，因此这些患者的患者更加异质， 更快，严重的临床表型。认知障碍与发生的突触丧失密切相关 在神经元丧失之前，显着表明突触功能障碍是关键治疗范围，并且 最终，多种有毒低聚物（αSyn，aβ和tau）的突触丧失，始于它们与PRPC的结合， 必须停止。我们的结果表明，RAP-103（一种小的口服肽CCR5拮抗剂）可能阻止两者 αSyn和Aβ介导的脊柱和啮齿动物神经元中的突触丧失，通过阻止PRPC激活 破坏微管，脊柱结构和突触功能。 RAP-103受保护的啮齿动物和人类神经元 来自αSyn和Aβ诱导的损失的刺和突触，以及对人αSynateAnimal的试点研究 型号6116，防止了认知缺陷。通过与神经元CCR5结合，RAP-103发挥了变构性 对膜结合的PRPC/NOX复合物激活的抑制作用，以阻止多个有毒的低聚物以停止， 可能会逆转，包括LBD在内的ADRD的突触丧失和认知能力下降。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确定的体内研究 通过脑组织化学分析与ADRD相关的密度和疾病生物标志物。我们将比较体内 使用[18f] Synvest-1作为一个活性动物SV2A PET成像的突触密度的组织化学分析作为一个 突触发生的定量生物标志物。我们将通过口服剂量从第6个月到第7个月进行RAP-103 动物经历突触丧失。我们将确定RAP-103对大脑突触密度标记的影响 皮质和海马通过定量方法测量突触素1的表达，一种突触囊泡 蛋白质和SVA2，PET成像示踪剂的靶标，并正常于神经元密度，并在前 确定了感兴趣的地区。我们还将通过测量RAP-103对疾病生物标志物的影响 神经原纤维缠结的数量，低聚tau，PTHR231TAU，多聚体总αSyn和PSER129 αSyn。成功完成目标将支持RAP-103的进一步发展，以保护突触保护 效果并建议将SV2A PET成像与[18F] Synvest-1作为定量生物标志物 ADRD中的突触发生，然后可以与生物标志物和认知益处相关 测试。