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.

项目总结 SorLA是通过GWAS分析确定的阿尔茨海默病(AD)的遗传危险因素。虽然 索拉已被证明管制应用程序交易，并由此产生β一代，一种正常的生物学 SorLA的功能仍然难以捉摸。在AD中，SorLA很可能介导了额外的神经保护作用； 鉴于已通过整个外显子组在SorLA中发现了大量突变的编码变体 在AD队列中进行测序，这些突变可能扰乱SorLA依赖的神经保护，或者通过 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，Sorla发挥了 通过结合和抑制可能的Aβ受体如EphA4的激活来限制神经保护作用 突触毒素EphA4的激活和Aβ暴露的认知损害。我们还展示了 SorLA在促进轴突生长和再生中的作用以及神经营养的SorLA结合配体 头部激活剂(HA)和神经降压素(NT)等“SorLA配体”可介导神经突起 以一种依赖于Sorla的方式增强。综上所述，这些结果暗示了SorLA在 增强突触功能，促进轴突生长和再生。这项研究的总体目标是 鉴定SOLA依赖抵抗β突触毒性的机制，并确定 增强SorLA介导的神经保护机制是否能改善突触和认知 阿尔茨海默病和唐氏综合征(DS)等A-β依赖神经退行性模型的损害。 SorLA与调节突触功能的受体之间的相互作用，如EphA4和TrkB，可能 用β突触毒性驱动索拉酸依赖的神经保护。使用包含全面的 一组早发和晚发AD相关突变变异体，我们将确定 突变可以影响SorLA与TrkB或神经营养配体的相互作用，并表征 Sorla在这些变异体中相互作用。鉴于SorLA可以通过β暴露增强突触功能，我们 将确定营养神经的SorLA配体是否可以增强突触LTP反应和认知 海马区立体定向A-β联合注射的作用。我们还提出了类似于AD的证据， 衰老的DS小鼠模型显示出类似的EphA4激活，表明EphA4可能驱动某些方面的 DS的突触毒性。我们将确定在DS小鼠模型中过表达转基因SorLA是否可以 减少DS小鼠模型中突触毒性EphA4的激活和突触/认知障碍。最后，我们将 确定通过立体定向输送SorLA配体进行的SorLA神经保护是否可以逆转或 应用二价SorLA/EphA4交联剂减轻AD模型小鼠突触/认知功能障碍 确定加强神经保护性SorLA/EphA4相互作用的多肽是否可以 阿尔茨海默病小鼠的突触保护作用。综上所述，这些结果将暗示Sorla在 神经保护，并可能涉及Aβ毒性的突触增强的新模式。