Tau-Fyn Interaction and Alzheimer's Disease

Tau-Fyn 相互作用与阿尔茨海默病

基本信息

  • 批准号:
    10292907
  • 负责人:
  • 金额:
    $ 1.62万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-01 至 2021-10-31
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Alzheimer’s disease (AD) is the leading cause of dementia worldwide and its impact will increase exponentially as the population ages. New therapeutic approaches are desperately needed to treat AD. The microtubule- associated protein Tau is has been heavily studies because it aggregates into neurofibrillary tangles within neurons, one of the hallmarks of AD. Genetic knockout of Tau is protective in several models of AD, highlighting its potential as a therapeutic target for AD. Interestingly, Tau reduction also prevents network hyperexcitability, which occurs early in AD and may contribute to neurodegeneration, in these models. Similarly, in a primary neuron culture system, Tau reduction prevents amyloid-β (Aβ) toxicity and glutamate or NMDA-induced excitotoxicity. In short, Tau reduction is protective in a variety of systems, but the mechanism by which it does so is currently unknown. Tau’s central proline-rich region, which is hyperphosphorylated in AD, has several PxxP motifs that mediate binding with SH3 domain–containing proteins including the nonreceptor tyrosine kinase Fyn. Fyn is also an important mediator of network hyperexcitability, as it phosphorylates AMPA and NMDA receptors to strengthen their signaling and regulates dendritic spine dynamics. Exogenous Aβ activates Fyn at the postsynaptic density, leading to NMDAR phosphorylation and excitotoxicity in neurons. Diverse evidence indicates that Tau’s interaction with Fyn could be a critical mediator of Aβ toxicity. Genetic knockout of either Tau or Fyn prevents Aβ toxicity in primary neurons, hyperphosphorylated Tau has a higher affinity for Fyn, and Tau mediates trafficking of Fyn to dendrites in vivo, leading to Aβ-induced cognitive deficits and network hyperexcitability. However, the idea that the Tau-Fyn interaction is a critical mediator of Aβ toxicity has not been directly tested, which is the goal of this project. My overarching hypothesis is that the Tau-Fyn interaction is a critical mediator of Aβ-induced structural and functional abnormalities. I will test this hypothesis using a peptide inhibitor of the Tau-Fyn interaction, Tau-PxxP5/6, developed by previous members of the Roberson lab. I developed a proximity ligation-based assay to confirm that Tau-PxxP5/6 inhibits endogenous Tau-Fyn interaction in situ and found that it prevents Aβ-induced neurite degeneration and membrane trafficking dysfunction. Here, I will determine if Tau-PxxP5/6 prevents Aβ-induced deficits in dendritic spine morphology using 3D morphometric analysis and Aβ- and gabazine-induced network hyperexcitability using multi-electrode arrays. I will also determine if the Fyn-binding region of Tau is the critical region of Tau that mediates Aβ toxicity by transducing Tau knockout neurons with different mutated Tau constructs to prevent Fyn binding. In addition to in vitro studies, I will determine if Tau-PxxP5/6 prevents cognitive deficits, epileptiform activity and seizure susceptibility in vivo using the hAPPJ20 mouse model of AD. The proposed work will provide insights into the molecular mechanisms of Aβ toxicity and could provide a promising therapeutic strategy to treat AD.
项目总结/文摘

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Jonathan R Roth其他文献

Jonathan R Roth的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

相似海外基金

Role of PSD-95-linked PDE4A5 in Regulation of AMPA Receptors
PSD-95 连接的 PDE4A5 在 AMPA 受体调节中的作用
  • 批准号:
    10829146
  • 财政年份:
    2023
  • 资助金额:
    $ 1.62万
  • 项目类别:
The role of AMPA receptors in critical period plasticity in the auditory cortex
AMPA 受体在听觉皮层关键期可塑性中的作用
  • 批准号:
    RGPIN-2018-06552
  • 财政年份:
    2022
  • 资助金额:
    $ 1.62万
  • 项目类别:
    Discovery Grants Program - Individual
In vivo Probe for ionotropic glutamate signaling system: AMPA receptors
离子型谷氨酸信号系统体内探针:AMPA 受体
  • 批准号:
    10584340
  • 财政年份:
    2022
  • 资助金额:
    $ 1.62万
  • 项目类别:
The role of AMPA receptors in critical period plasticity in the auditory cortex
AMPA 受体在听觉皮层关键期可塑性中的作用
  • 批准号:
    RGPIN-2018-06552
  • 财政年份:
    2021
  • 资助金额:
    $ 1.62万
  • 项目类别:
    Discovery Grants Program - Individual
The role of AMPA receptors in critical period plasticity in the auditory cortex
AMPA 受体在听觉皮层关键期可塑性中的作用
  • 批准号:
    RGPIN-2018-06552
  • 财政年份:
    2020
  • 资助金额:
    $ 1.62万
  • 项目类别:
    Discovery Grants Program - Individual
Binding of Endophilin Endocytic Proteins to AMPA Receptors and Neuronal Voltage-gated Potassium (Kv) Channels: Regulation of Synaptic Plasticity
内亲素内吞蛋白与 AMPA 受体和神经元电压门控钾 (Kv) 通道的结合:突触可塑性的调节
  • 批准号:
    RGPIN-2015-03850
  • 财政年份:
    2019
  • 资助金额:
    $ 1.62万
  • 项目类别:
    Discovery Grants Program - Individual
The missing link: Opioid modulation of AMPA receptors
缺失的环节:阿片类药物对 AMPA 受体的调节
  • 批准号:
    2253144
  • 财政年份:
    2019
  • 资助金额:
    $ 1.62万
  • 项目类别:
    Studentship
Calcium-permeable AMPA receptors and their auxiliary subunits: pharmacological and molecular intervention in health and disease
钙渗透性 AMPA 受体及其辅助亚基:健康和疾病的药理学和分子干预
  • 批准号:
    MR/T002506/1
  • 财政年份:
    2019
  • 资助金额:
    $ 1.62万
  • 项目类别:
    Research Grant
The role of AMPA receptors in critical period plasticity in the auditory cortex
AMPA 受体在听觉皮层关键期可塑性中的作用
  • 批准号:
    RGPIN-2018-06552
  • 财政年份:
    2019
  • 资助金额:
    $ 1.62万
  • 项目类别:
    Discovery Grants Program - Individual
Life cycle of AMPA receptors under acute metabolic stress
急性代谢应激下 AMPA 受体的生命周期
  • 批准号:
    411538084
  • 财政年份:
    2018
  • 资助金额:
    $ 1.62万
  • 项目类别:
    Research Units
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了