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: 10404609
• 负责人: Timothy Yikai Huang
• 金额: $ 68.13万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404609
• 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; insight; limb regeneration; mouse model; mutant; neurite growth; neuroprotection; neurotoxic; novel; overexpression; protein protein interaction; receptor; repaired; response; risk variant; sortilin; synaptic function; trafficking; wound

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 SORLA是通过GWAS分析确定的阿尔茨海默病（AD）的遗传风险因素。虽然 SORLA已被证明可以调节APP运输和随后的Aβ生成，这是一种正常的生物学行为。 SORLA的功能仍然难以捉摸。SORLA可能在AD中介导额外的神经保护作用; 鉴于已经通过整个外显子组在SORLA中鉴定了许多突变编码变体， 在AD队列中，这些突变可能会干扰SORLA依赖的神经保护， 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 通过结合和抑制推定的Aβ受体如EphA 4的活化以限制 突触毒性EphA 4活化和Aβ暴露的认知障碍。我们还展示了一个角色， SORLA在促进神经突生长和再生中的作用，以及神经营养性SORLA结合配体 SORLA配体（“SORLA配体”）如头部激活物（HA）和神经降压素（NT）肽可以介导神经突的生长。 以SORLA依赖的方式增强。总之，这些结果暗示了SOLLA在以下方面的新作用： 增强突触功能、神经突生长和再生。本研究的总体目标是 表征SORLA依赖性抗Aβ突触毒性的机制，并确定 增强SORLA介导的神经保护机制是否可以改善突触和认知功能 在Aβ依赖性神经退行性模型如AD和唐氏综合征（DS）中的损伤。 SORLA与调节突触功能的受体（如EphA 4和TrkB）之间的相互作用可能 通过Aβ突触毒性驱动SORLA依赖性神经保护作用。使用包含全面的 一组SORLA-FLAG早发和迟发AD相关突变变体，我们将确定是否 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与TrkB或神经营养配体之间的差异。 在这些变体中的SORLA相互作用体。鉴于SORLA可以增强Aβ暴露的突触功能，我们 将确定神经营养SORLA配体是否可以增强突触LTP反应和认知功能。 功能与立体定向Aβ共注射到海马。我们还提出证据表明，类似于AD， 老年DS小鼠模型显示出类似的EphA 4活化，表明EphA 4可能驱动EphA 4的某些方面。 DS中的突触毒性。我们将确定转基因SORLA在DS小鼠模型中的过表达是否能 减少DS小鼠模型中的突触毒性EphA 4活化和突触/认知损伤。最后，我们将 确定通过立体定向递送SORLA配体的SORLA神经保护是否可以逆转或 减轻AD小鼠模型中的突触/认知损害，并使用二价SORLA/EphA 4交联 肽，以确定增强的神经保护性SORLA/EphA 4相互作用是否可以赋予 AD小鼠的突触保护作用。总之，这些结果将暗示SOLLA在以下方面的新作用： 神经保护作用，并可能涉及新的突触增强模式与Aβ毒性。