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Tau acetylation in Alzheimer's disease

阿尔茨海默病中的 Tau 乙酰化

基本信息

批准号：
9915831
负责人：
Li Gan
金额：
$ 58.82万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2018-09-13 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9915831
关键词：
AMPA Receptors ANK3 gene Acetylation Actins Address Affect Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Amyloid beta-Protein Anatomy Autopsy Axon Binding Proteins Brain Bypass CRISPR/Cas technology Chemicals Clinical Cognition Cognitive deficits Collaborations Cytoskeleton Dementia Dendrites Dendritic Spines Disease Dissection Dynein ATPase Exhibits Fluorescence Recovery After Photobleaching Gene Transfer Goals Heterogeneity Human Image Impaired cognition Impairment Kidney Lead Link Long-Term Potentiation Measures Mediating Memory Memory Loss Memory impairment Microscopy Microtubules Molecular Movement Mus Neurons Optics Paclitaxel Pathogenesis Pathogenicity Pathology Pharmacology Photobleaching Play Pluripotent Stem Cells Plus End of the Microtubule Proteins Rattus Recovery Resolution Rodent Role Scaffolding Protein Signal Transduction Sorting - Cell Movement Structural Protein Structure Synapses Synaptic plasticity Tauopathies Testing Therapeutic Toxic effect Transgenic Organisms Translating Treatment Efficacy Tubulin Viral base betaIV spectrin cognitive enhancement cognitive function dendrin genome editing hippocampal atrophy imaging study in vivo induced pluripotent stem cell insight memory encoding mouse model mutant novel novel therapeutics overexpression postsynaptic prevent reconstruction single molecule spatial memory synaptic function synaptopodin tau Proteins tau aggregation tau mutation tau-1 trafficking

项目摘要

The cognitive decline in Alzheimer's disease (AD) correlates with tau pathology or CSF tau. However, the pathogenic tau species and the mechanisms underlying tau toxicity in AD remain elusive. Our recent study points to important pathogenic roles for aberrantly acetylated tau (ac-tau) species, whose levels are elevated in NFTs, and the elevation is associated with cognitive impairment in AD. A critical trigger of tau-mediated toxicity in AD is elevated somatodendritic tau. We showed that tau acetylation on K274 and K281 destabilizes the barrier in the axon initial segment (AIS) and elevates levels of somatodendritic tau. Mice expressing mutant tau that mimics acetylation (KQ) exhibited impaired synaptic plasticity and spatial memory. Our study further linked tau-mediated synaptic plasticity impairment with deficiency in KIBRA, post-synaptic scaffolding protein. While KIBRA is reduced in AD brains, elevating KIBRA expression prevented KQ-induced LTP deficits in rat neurons. We propose to further dissect the mechanisms underlying ac-tau-mediated deficits in synaptic plasticity and memory by combining human neuron and mouse models. In Aim 1, we will focus on the effects of ac-tau on the AIS, which plays a critical role in restricting axonal protein from somatodendritic compartments in human neurons. We will use our newly established inducible pluripotent stem cells (iPSCs)-derived human neuron platform and CRISPR/cas9 genomic editing to establish isogenic lines that express acetyl-mimicking tau at endogenous levels. We will then collaborate with Dr. Ke Xu and use stochastic optical reconstruction microscopy (STORM) to image AIS structural proteins and tau distribution in axons and dendrites of human neurons at single-molecule resolution. In Aim 2, we will directly determine whether ac-tau gains access to dendritic spines by destabilizing the AIS using a combination of STORM and live imaging. In human iPSC neurons, we will assess the effects of ac-tau on microtubule dynamics and stability, particularly at AIS, using fluorescence recovery after photobleaching. We will then compare the extent to which WT and KQ tau cross the AIS and determine whether restoring AIS barrier function specifically using caged taxol would normalize tau distribution. In Aim 3, we will dissect the post-synaptic mechanisms underlying tau-mediated synaptic plasticity and cognition. To determine if deficiency in KIBRA is a driver in tau-mediated synaptic deficits, we test if lowering KIBRA levels is sufficient to cause tau-mediated synaptic deficits by deleting one allele of KIBRA in mice expressing human wildtype tau. Various domains of KIBRA interact directly with postsynaptic proteins, including PICK1, synaptopodin, dendrin, dynein, and PKMζ, to regulate actin cytoskeleton and/or AMPAR trafficking. Using KIBRA mutants containing specific signaling domains, we propose to identify which KIBRA-mediated signaling plays a critical role in tau-mediated synaptic toxicity. By combining mechanistic dissection in human iPSC-derived neurons and in vivo circuit studies in mouse models, we expect to gain novel insights that can be translated into therapies to counteract tau-mediated cognitive decline.

阿尔茨海默病(AD)的认知能力下降与tau病理或脑脊液tau相关。然而，在阿尔茨海默病中，致病的tau种类和tau毒性的机制仍然不清楚。我们最近的研究指出了异常乙酰化的tau(ac-tau)物种的重要致病作用，其水平在 NFTS，这种升高与AD的认知损害有关。Tau介导的毒性的关键触发因素阿尔茨海默病患者躯体树突状细胞tau升高。我们发现K274和K281上的tau乙酰化会破坏细胞的稳定性。轴突起始段(AIS)的屏障，并增加躯体树突状细胞tau的水平。表达突变tau蛋白的小鼠模拟乙酰化(KQ)表现出突触可塑性和空间记忆受损。我们的研究进一步联系到突触后支架蛋白Kibra缺乏时tau介导的突触可塑性损害。而当 Kibra在AD大脑中减少，上调Kibra的表达可以阻止KQ诱导的大鼠神经元LTP缺失。我们建议进一步剖析Ac-tau介导的突触可塑性缺陷和通过结合人类神经元和小鼠模型进行记忆。在目标1中，我们将重点研究Ac-tau对 AIS在限制人类躯体树突间的轴突蛋白中起着关键作用神经元。我们将使用我们新建立的可诱导多能干细胞(IPSCs)来源的人类神经元 Platform和CRISPR/Cas9基因组编辑，以建立表达乙酰基模拟tau的等基因系内源性水平。然后我们将与柯旭博士合作，使用随机光学重建显微镜(STORM)成像AIS结构蛋白和tau在人轴突和树突中的分布单分子分辨率的神经元。在目标2中，我们将直接确定ac-tau是否获得通过使用风暴和现场成像相结合的方式破坏AIS的稳定，树突棘。在人类IPSC中，我们将评估ac-tau对微管动力学和稳定性的影响，特别是在AIS，使用光漂白后的荧光恢复。然后我们将比较WT和KQ Tau的交叉程度并确定专门使用笼养紫杉醇恢复AIS屏障功能是否会正常化陶氏分布。在目标3中，我们将剖析tau介导的突触的突触后机制。可塑性和认知性。为了确定Kibra缺陷是否是tau介导的突触缺陷的驱动因素，我们测试降低Kibra水平是否足以导致tau介导的突触缺陷，方法是删除一个等位基因在表达人野生型tau的小鼠中发现Kibra。Kibra的各个区域与突触后直接相互作用调节肌动蛋白细胞骨架和/或肌动蛋白的蛋白质，包括PICK1、突触素、树突状蛋白、动力蛋白和PKMζ 安帕尔贩卖。使用包含特定信号域的Kibra突变体，我们建议识别哪些 Kibra介导的信号在tau介导的突触毒性中起着关键作用。通过结合机械学在人类IPSC来源的神经元的解剖和小鼠模型的活体电路研究中，我们预计将获得可以转化为治疗的新见解，以对抗tau介导的认知衰退。