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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）中的认知下降与tau病理学或CSF tau相关。但致病性tau种类和AD中tau毒性的潜在机制仍然难以捉摸。我们最近的研究指出了异常乙酰化tau（ac-tau）物质的重要致病作用，其水平在 NFT，并且升高与AD中的认知障碍相关。tau蛋白介导毒性的关键触发因素是体树突状tau蛋白升高。我们发现，在K274和K281上的tau乙酰化使蛋白质不稳定。轴突起始段（AIS）中的屏障并升高体树突tau的水平。表达突变tau的小鼠模拟乙酰化（KQ）的神经元表现出受损的突触可塑性和空间记忆。我们的研究进一步联系了 tau蛋白介导的突触可塑性损伤伴突触后支架蛋白KIBRA缺乏。而 KIBRA在AD脑中减少，升高KIBRA表达可防止大鼠神经元中KQ诱导的LTP缺陷。我们建议进一步剖析ac-tau介导的突触可塑性缺陷的机制，通过结合人类神经元和小鼠模型来记忆。在目标1中，我们将重点关注ac-tau对 AIS在限制轴突蛋白进入人体体树突区室中起关键作用神经元我们将使用我们新建立的诱导性多能干细胞（iPSC）衍生的人类神经元平台和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。然后我们将与徐克博士合作，利用STORM显微镜对AIS结构蛋白和tau蛋白在人类神经元轴突和树突中的分布进行成像。单分子分辨率的神经元。在目标2中，我们将直接确定ac-tau是否能够获得树突棘通过使用STORM和实时成像的组合使AIS不稳定。在人类iPSC中神经元，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交叉的程度，并确定是否恢复AIS屏障功能，特别是使用笼紫杉醇将正常化 τ分布在目标3中，我们将剖析tau蛋白介导的突触后机制，可塑性和认知为了确定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水平是否足以通过删除一个等位基因引起tau介导的突触缺陷，表达人野生型tau的小鼠中的KIBRA。KIBRA的不同结构域直接与突触后神经元相互作用。蛋白质，包括PICK 1、突触足蛋白、树突蛋白、动力蛋白和PKM β，以调节肌动蛋白细胞骨架和/或 AMPAR走私。使用含有特定信号传导结构域的KIBRA突变体，我们建议鉴定 KIBRA介导的信号传导在tau介导的突触毒性中起关键作用。通过结合机械在人类iPSC衍生神经元的解剖和小鼠模型的体内电路研究中，我们期望获得新的见解，可以转化为治疗，以抵消tau介导的认知下降。