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痴呆占65岁以上患者所有痴呆的25%， β淀粉样蛋白（Aβ）、tau和α-突触核蛋白（αSyn）引起的共病病理学证据。AD的程度- 路易体痴呆（LBD）的相关病理学在50%的PDD和超过70%的PDD中是中度或重度的。 DLB患者伴随AD相关病理，因此这些患者经历更异质的， 更快和严重的临床表型。认知障碍与突触丧失密切相关， 这表明突触功能障碍是关键的治疗靶点， 最终由多种毒性寡聚体（αSyn，Aβ和tau）引起的突触丧失，始于它们与PrPc的结合， 必须阻止我们的研究结果表明，RAP-103，一种小的口服肽CCR 5拮抗剂，有效地阻止了这两种作用。 αSyn和Aβ通过阻断PrPc激活介导啮齿动物和人类神经元中的棘和突触丢失， 破坏微管、棘结构和突触功能。RAP-103保护啮齿动物和人神经元 αSyn和Aβ诱导的丢失的棘和突触，以及在表达人αSyn的动物的初步研究中， 模型线6116，防止认知缺陷。通过与神经元CCR 5结合，RAP-103发挥变构作用。 对膜结合PrPc/NOX复合物活化的抑制作用阻断多种毒性寡聚体的停止， 可能逆转ADRD包括LBD的突触丢失和认知下降。利用TG 4510混合α- 在突触/Tau病动物模型中，我们将进行RAP-103对突触的保护作用的确定性体内研究。 密度和疾病生物标志物相关的ADRD通过脑组织化学分析。我们将在体内进行比较 用[18 F]SynVesT-1作为突触密度标记物对活体动物SV 2A PET成像突触密度的组织化学分析 突触发生的定量生物标志物。我们将从第6个月至第7个月通过口服给药给予RAP-103， 动物经历突触丧失。我们将确定RAP-103对脑突触密度标记物的影响， 通过定量方法测量突触囊泡突触素1的表达， 蛋白和SVA 2，PET成像示踪剂的靶点，并在预处理中用NeuN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RAP-103对疾病生物标志物的影响。 神经元缠结-NFT负荷、寡聚Tau、pThr 231 Tau、多聚体总αSyn和pSer 129的数量 αSyn。目标的成功完成将支持RAP-103用于突触保护的进一步开发 并建议使用SV 2A PET成像与[18 F]SynVesT-1作为定量生物标志物， ADRD中的突触发生，然后可以将其与用于人类的生物标志物和认知益处相关联 试验.