Novel roles for the Alzheimer's Disease (AD) risk gene, SORLA in neuroprotection in AD

阿尔茨海默病 (AD) 风险基因 SORLA 在 AD 神经保护中的新作用

• 批准号: 9788245
• 负责人: Timothy Yikai Huang
• 金额: $ 68.23万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788245
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Attenuated; Behavioral; Binding; Biochemical; Biological Assay; Biological Process; Brain; Cell model; Cell surface; Code; Cognitive; Cognitive deficits; Defect; Disease; Down Syndrome; Etiology; Exposure to; Fresh Water; Functional disorder; Generations; Genetic; Head; Hippocampus (Brain); Hydrozoa; Impaired cognition; Impairment; Injections; Late Onset Alzheimer Disease; Libraries; Ligand Binding; Ligands; Mediating; Modeling; Mus; Mutation; Natural regeneration; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurons; Neurotensin; Onset of illness; Pathologic; Pathway interactions; Peptides; Physiological; Process; Proteolytic Processing; Proteomics; Receptor Activation; Reporting; Resistance; Risk Factors; Role; Signal Transduction; Synapses; Transgenic Organisms; Variant; Vertebral column; abeta toxicity; age related; aged; cognitive function; cohort; combinatorial; crosslink; density; exome sequencing; extracellular; genetic risk factor; genome wide association study; in vivo; inhibitor/antagonist; insight; limb regeneration; mouse model; mutant; neurite growth; neuroprotection; neurotoxic; novel; overexpression; protein protein interaction; receptor; repaired; response; risk variant; sortilin; synaptic function; trafficking

PROJECT SUMMARY SORLA is a genetic risk factor for Alzheimer’s disease (AD) identified through GWAS analysis. Although SORLA has been shown to regulate APP trafficking and consequent Aβ generation, a normal biological function for SORLA remains elusive. It is likely that SORLA mediates additional neuroprotective effects in AD; given that numerous mutational coding variants have been identified in SORLA through whole exome sequencing in AD cohorts, these mutations may perturb SORLA-dependent neuroprotection, either through functional protein-protein interaction or SORLA localization. Our preliminary results indicate that SORLA exerts neuroprotective effects by binding and inhibiting the activation of putative Aβ receptors such as EphA4 to limit synaptotoxic EphA4 activation and cognitive impairment with Aβ exposure. We also demonstrate a role for SORLA in enhancing neurite outgrowth and regeneration, and that neurotrophic SORLA-binding ligands (“SORLA ligands”) such as head activator (HA) and neurotensin (NT) peptides can mediate neurite enhancement in a SORLA-dependent manner. Together, these results implicate new roles for SORLA in enhancing synaptic function, neurite outgrowth and regeneration. The overall objective of this study is to characterize mechanisms underlying SORLA-dependent resistance to Aβ synaptotoxicity, and to determine whether enhancing SORLA-mediated neuroprotective mechanisms can ameliorate synaptic and cognitive impairment in Aβ-dependent neurodegenerative models such as AD and Down Syndrome (DS). Interactions between SORLA and receptors that modulate synaptic function such as EphA4 and TrkB, likely drive SORLA-dependent neuroprotection with Aβ synaptotoxicity. Using a library comprising a comprehensive set of SORLA-FLAG early and late onset AD-associated mutational variants, we will determine whether mutations can affect SORLA interactions with TrkB, or neurotrophic ligands, and characterize differences in the SORLA interactome in these variants. Given that SORLA can enhance synaptic function with Aβ exposure, we will determine whether neurotrophic SORLA ligands can enhance synaptic LTP response and cognitive function with stereotactic Aβ co-injection into the hippocampus. We also present evidence that similar to AD, aged DS mouse models show similar EphA4 activation, indicating that EphA4 may drive some aspects of synaptotoxicity in DS. We will determine whether transgenic SORLA overexpression in DS mouse models can reduce synaptotoxic EphA4 activation and synaptic/cognitive impairment in a DS mouse model. Lastly, we will determine whether SORLA neuroprotection through stereotactic delivery of SORLA ligands can reverse or attenuate synaptic/cognitive impairment in AD mouse models and use bivalent SORLA/EphA4 crosslinking peptides to determine whether reinforcing neuroprotective SORLA/EphA4 interactions can confer synaptoprotective effects in AD mice. Together, these results will implicate new roles for SORLA in neuroprotection and may implicate new modes of synaptic enhancement with Aβ toxicity.

项目摘要 索拉是通过GWAS分析确定的阿尔茨海默氏病（AD）的遗传危险因素。虽然 Sorla已被证明可以调节APP运输和随之而来的Aβ产生，这是一种正常的生物学 索拉的功能仍然难以捉摸。索拉很可能介导了AD中的其他神经保护作用。 鉴于已经通过整个外显子在索拉（Sorla）中发现了许多突变编码变体 在AD队列中进行测序，这些突变可能会通过 功能性蛋白质 - 蛋白质相互作用或Sorla定位。我们的初步结果表明索拉执行 神经保护作用通过结合和抑制推定的Aβ受体（例如epha4）的激活以限制 突触毒素EPHA4激活和Aβ暴露的认知障碍。我们还展示了 索拉（Sorla （“ Sorla配体”），例如头部激活剂（HA）和神经素（NT）Pepperides可以介导神经蛋白 以索拉的依赖方式增强。这些结果在一起，暗示了索拉在 增强突触功能，神经落生和再生。这项研究的总体目的是 表征了索拉依赖性抗Aβ突触毒性的机制，并确定 增强索拉介导的神经保护机制是否可以改善突触和认知 Aβ依赖性神经退行性模型（例如AD和唐氏综合征（DS））的损害。 索拉与调节突触功能（例如epha4和trkb）的接收器之间的相互作用，可能 具有Aβ突触毒性的驱动索拉依赖性神经保护。使用图书馆完成综合 一组Sorla-FLAG早期和晚期发作广告相关的突变变体，我们将确定是否确定是否是否 突变会影响索拉与TRKB或神经营养配体的相互作用，并表征了差异 这些变体中的索拉相互作用。鉴于Sorla可以通过Aβ暴露增强突触功能，我们 将确定神经营养性索拉配体是否可以增强突触LTP反应和认知 立体定向Aβ共注入海马。我们还提供了类似于AD的证据 老化的DS鼠标模型显示出相似的EPHA4激活，表明EPHA4可能会驱动 DS中的突触毒性。我们将确定DS鼠标模型中的转基因Sorla过表达是否可以 DS小鼠模型中的突触毒素EPHA4激活和突触/认知障碍。最后，我们会的 通过立体定向递送Sorla配体可以逆转或 衰减AD鼠标模型中的突触/认知障碍，并使用二价Sorla/Epha4交联 肽以确定增强神经保护性Sorla/Epha4相互作用是否可以召集 AD小鼠的突触保护作用。这些结果将共同执行索拉的新角色 神经保护作用，可能暗示着具有Aβ毒性的新型突触增强模式。