Functional Effects of PDE11A Alzheimer's-Associated Variants

PDE11A 阿尔茨海默病相关变体的功能影响

基本信息

  • 批准号:
    10494545
  • 负责人:
  • 金额:
    $ 38.62万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-02-15 至 2023-11-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY: Functional Effects of PDE11A Alzheimer’s Disease (AD)-Associated Variants This parent grant explores how age-related increases in expression and ectopic localization of the enzyme Phosphodiesterase 11A (PDE11A) drive age-related cognitive decline (ARCD). PDE11A is of particular interest in the context of aging and AD because its expression in brain is enriched in the hippocampal formation—a region that is critical for episodic memory and is severely impaired in AD. We find PDE11A expression increases with age in the rodent and human hippocampus and is further elevated in hippocampus of demented vs. non-demented aged humans with a history of TBI. We have established that these age-related increases in PDE11A are ectopically enriched in hippocampal “ghost axons”—that is, axonal terminals that are so densely packed with PDE11A protein that other axonal proteins are occluded. Through mutational analyses, we have identified intramolecular signals responsible for these age-related increases in PDE11A expression and its ectopic localization and have shown that Pde11a knockout mice are protected against ARCD. Given that advanced age is the strongest risk factor for dementia, coupled with the fact that these PDE11A “ghost axons” are particularly reminiscent of tau proteinopathies that are associated with ADRDs, it is highly interesting that 2 rare PDE11A variants (i.e., R202H and L756Q) have recently been associated with early-onset AD. The impact of these mutations on PDE11A function were not measured directly; however, expression of the mutants increased phosphorylation of recombinant tau in an in vitro assay. This PDE11A mutation-induced increase in p-tau is consistent with the pathophysiology observed in ADRD brains; however, it suggests a PDE11A loss-of- function that stands in direct contrast to the PDE11A gain-of-function that we observe with normal aging. As such, we test the overarching hypothesis that AD-related PDE11A mutations alter catalytic activity and/or subcellular compartmentalization of PDE11A in a manner that fundamentally differs from aging itself, thereby producing biochemical and behavioral deficits worse than those seen with normal aging. Across the 2 aims, we take an integrative approach by coupling in vivo and in vitro genetic manipulations with behavioral, physiological, and biochemical endpoints. In Specific Aim 1, we determine how the AD-related PDE11A variants alter protein expression, catalytic activity, subcellular compartmentalization, phosphorylation, and downstream signaling of PDE11A in a hippocampal cell line that endogenously expresses tau and recapitulates PDE11A age-related proteinopathies. In Specific Aim 2, we determine if elevated expression of these PDE11A AD-associated variants in mouse hippocampus produces more widespread cognitive decline than elevated expression of wild-type PDE11A.These innovative studies will provide much needed insight into the functional consequences of these AD-related mutations and are consistent with the Division of Neuroscience’s goal to understand how the processes of ARCD intersect with the development of AD.
项目总结:PDE 11 A阿尔茨海默病(AD)相关变体的功能影响 这个家长补助金探讨如何与年龄有关的增加表达和异位定位的酶 磷酸二酯酶11 A(PDE 11 A)驱动年龄相关的认知衰退(ARCD)。PDE 11 A特别令人感兴趣 在衰老和AD的背景下,因为其在脑中的表达在海马结构中富集, 该区域对情景记忆至关重要,在AD中严重受损。我们发现PDE 11 A表达 在啮齿类动物和人类海马中随着年龄的增长而增加,并且在痴呆患者的海马中进一步升高。 vs.有TBI病史的非痴呆老年人。我们已经确定,这些与年龄有关的增加, PDE 11 A异位富集在海马体的“幽灵轴突”中--也就是说, PDE 11 A蛋白包裹着其他轴突蛋白。通过突变分析, 确定了负责这些年龄相关的PDE 11 A表达增加的分子内信号, 异位定位,并显示Pde 11 a敲除小鼠对ARCD有保护作用。鉴于 高龄是痴呆症的最大危险因素,再加上这些PDE 11 A“幽灵轴突” 特别令人联想到与ADRD相关的tau蛋白病,非常有趣的是,2 罕见的PDE 11 A变体(即,R202 H和L756 Q)最近与早发性AD相关。的影响 没有直接测量这些突变对PDE 11 A功能的影响;然而,突变体的表达 体外试验中重组tau的磷酸化增加。这种PDE 11 A突变诱导的 p-tau与在ADRD脑中观察到的病理生理学一致;然而,它表明PDE 11 A缺失, 这与我们在正常老化中观察到的PDE 11 A功能获得形成直接对比。作为 因此,我们检验了AD相关PDE 11 A突变改变催化活性和/或 PDE 11 A的亚细胞区室化的方式与衰老本身根本不同, 从而产生比正常衰老更严重的生化和行为缺陷。 在这两个目标中,我们采取了一种综合方法,将体内和体外遗传操作与 行为、生理和生化终点。在具体目标1中,我们确定与AD相关的 PDE 11 A变体改变蛋白质表达、催化活性、亚细胞区室化、磷酸化 和内源性表达tau的海马细胞系中PDE 11 A的下游信号传导, 概括了PDE 11 A年龄相关的蛋白质病。在具体目标2中,我们确定是否升高的表达, 小鼠海马中的这些PDE 11 A AD相关变体产生更广泛的认知衰退 这些创新性的研究将提供急需的洞察力, 这些AD相关突变的功能性后果,并与 神经科学的目标是了解ARCD的过程如何与AD的发展交叉。

项目成果

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Michy Patrice Kelly其他文献

Michy Patrice Kelly的其他文献

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{{ truncateString('Michy Patrice Kelly', 18)}}的其他基金

Role of Cyclic Nucleotide Signaling in Age-related Decline of Social Memories
环核苷酸信号传导在年龄相关的社交记忆衰退中的作用
  • 批准号:
    10307444
  • 财政年份:
    2019
  • 资助金额:
    $ 38.62万
  • 项目类别:
Role of Cyclic Nucleotide Signaling in Age-related Decline of Social Memories
环核苷酸信号传导在年龄相关的社交记忆衰退中的作用
  • 批准号:
    10541235
  • 财政年份:
    2019
  • 资助金额:
    $ 38.62万
  • 项目类别:
Role of Cyclic Nucleotide Signaling in Age-related Decline of Social Memories
环核苷酸信号传导在年龄相关的社交记忆衰退中的作用
  • 批准号:
    10358500
  • 财政年份:
    2019
  • 资助金额:
    $ 38.62万
  • 项目类别:
Role of Cyclic Nucleotide Signaling in Age-Related Decline of Social Memories
环核苷酸信号传导在年龄相关的社交记忆衰退中的作用
  • 批准号:
    10541012
  • 财政年份:
    2019
  • 资助金额:
    $ 38.62万
  • 项目类别:
Compartmentalization of Cyclic Nucleotide Signaling in the Ventral Hippocampus
腹侧海马环核苷酸信号传导的区室化
  • 批准号:
    8889305
  • 财政年份:
    2014
  • 资助金额:
    $ 38.62万
  • 项目类别:
Compartmentalization of Cyclic Nucleotide Signaling in the Ventral Hippocampus
腹侧海马环核苷酸信号传导的区室化
  • 批准号:
    9270603
  • 财政年份:
    2014
  • 资助金额:
    $ 38.62万
  • 项目类别:
Compartmentalization of Cyclic Nucleotide Signaling in the Ventral Hippocampus
腹侧海马环核苷酸信号传导的区室化
  • 批准号:
    8759770
  • 财政年份:
    2014
  • 资助金额:
    $ 38.62万
  • 项目类别:
Selective Targeting of Phosphodiesterase 11A Transcription and Catalytic Activit
磷酸二酯酶 11A 转录和催化活性的选择性靶向
  • 批准号:
    8653311
  • 财政年份:
  • 资助金额:
    $ 38.62万
  • 项目类别:

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  • 批准号:
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CITICOLINE AND AGE ASSOCIATED MEMORY IMPAIRMENT
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  • 财政年份:
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CITICOLINE AND AGE ASSOCIATED MEMORY IMPAIRMENT
胞二磷胆碱与年龄相关的记忆障碍
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A study on the biological features of age-associated memory impairment (AAMI).
年龄相关记忆障碍(AAMI)生物学特征的研究。
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    Grant-in-Aid for Scientific Research (C).
CITICOLINE AND AGE ASSOCIATED MEMORY IMPAIRMENT
胞二磷胆碱与年龄相关的记忆障碍
  • 批准号:
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AGE-ASSOCIATED MEMORY IMPAIRMENT: COMMUNITY-BASED STUDY
与年龄相关的记忆障碍:基于社区的研究
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