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

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.
项目总结

项目成果

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Timothy Yikai Huang其他文献

Timothy Yikai Huang的其他文献

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{{ truncateString('Timothy Yikai Huang', 18)}}的其他基金

Elucidating a microgliaassociated role for SORLA in modulating AD pathogenesis
阐明 SORLA 在调节 AD 发病机制中的小胶质细胞相关作用
  • 批准号:
    10455261
  • 财政年份:
    2022
  • 资助金额:
    $ 68.23万
  • 项目类别:
Characterizing a potential role for TREM2 in modulating tau pathogenesis in response to Abeta
表征 TREM2 在响应 Abeta 调节 tau 发病机制中的潜在作用
  • 批准号:
    10360474
  • 财政年份:
    2021
  • 资助金额:
    $ 68.23万
  • 项目类别:
"A Novel Role for the UPR Component, ATF6 in AD-associated Neuroprotective Pathways"
“UPR 成分 ATF6 在 AD 相关神经保护途径中的新作用”
  • 批准号:
    10132964
  • 财政年份:
    2019
  • 资助金额:
    $ 68.23万
  • 项目类别:
"A Novel Role for the UPR Component, ATF6 in AD-associated Neuroprotective Pathways"
“UPR 成分 ATF6 在 AD 相关神经保护途径中的新作用”
  • 批准号:
    10563219
  • 财政年份:
    2019
  • 资助金额:
    $ 68.23万
  • 项目类别:
"A Novel Role for the UPR Component, ATF6 in AD-associated Neuroprotective Pathways"
“UPR 成分 ATF6 在 AD 相关神经保护途径中的新作用”
  • 批准号:
    10353397
  • 财政年份:
    2019
  • 资助金额:
    $ 68.23万
  • 项目类别:
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
  • 财政年份:
    2018
  • 资助金额:
    $ 68.23万
  • 项目类别:
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:
    9925791
  • 财政年份:
    2018
  • 资助金额:
    $ 68.23万
  • 项目类别:
Molecular pathobiology of soluble TREM2 in Alzheimer's disease
可溶性 TREM2 在阿尔茨海默病中的分子病理学
  • 批准号:
    10737172
  • 财政年份:
    2017
  • 资助金额:
    $ 68.23万
  • 项目类别:
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