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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目概要 SORLA 是通过 GWAS 分析确定的阿尔茨海默病 (AD) 的遗传风险因素。 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 SORLA 的功能仍然难以捉摸。SORLA 可能在 AD 中发挥额外的神经保护作用。鉴于通过整个外显子组在 SORLA 中鉴定出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以下方式扰乱 SORLA 依赖性神经保护：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 发挥作用。通过结合和抑制假定的 Aβ 受体（例如 EphA4）的激活来限制神经保护作用我们还证明了 Aβ 暴露导致的突触毒性 EphA4 激活和认知障碍。 SORLA 增强神经突生长和再生，以及神经营养性 SORLA 结合配体（“SORLA 配体”）如头部激活剂 (HA) 和神经降压素 (NT) 肽可以介导神经突总之，这些结果意味着 SORLA 在以下方面发挥了新的作用。增强突触功能、神经突生长和再生。表征 SORLA 依赖性 Aβ 突触毒性抗性的机制，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 Aβ 依赖性神经退行性模型（如 AD 和唐氏综合症 (DS)）的损伤。 SORLA 与调节突触功能的受体（例如 EphA4 和 TrkB）之间的相互作用可能使用包含综合性库的 Aβ 突触毒性驱动 SORLA 依赖性神经保护。一组 SORLA-FLAG 早期和晚期 AD 相关突变变异，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，并表征这些变体中的 SORLA 相互作用组鉴于 SORLA 可以通过 Aβ 暴露增强突触功能，我们将确定神经营养性 SORLA 配体是否可以增强突触 LTP 反应和认知我们还提供了与 AD 类似的证据，老年 DS 小鼠模型显示出类似的 EphA4 激活，表明 EphA4 可能驱动某些方面我们将确定转基因 SORLA 在 DS 小鼠模型中的过度表达是否可以发挥作用。减少 DS 小鼠模型中的突触毒性 EphA4 激活和突触/认知障碍。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/认知障碍并使用二价 SORLA/EphA4 交联肽来确定增强神经保护作用的 SORLA/EphA4 相互作用是否可以赋予总之，这些结果将暗示 SORLA 在 AD 小鼠中的新作用。神经保护作用，并可能涉及 Aβ 毒性突触增强的新模式。