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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) 中的认知能力下降与 tau 蛋白病理学或脑脊液 tau 蛋白相关。然而，致病性 tau 蛋白种类以及 AD 中 tau 蛋白毒性的机制仍然难以捉摸。我们最近的研究指出异常乙酰化 tau (ac-tau) 物种的重要致病作用，其水平在 NFT，其升高与 AD 认知障碍有关。 tau 介导的毒性的关键触发因素 AD 中体细胞树突 tau 蛋白升高。我们发现 K274 和 K281 上的 tau 乙酰化会破坏轴突起始段 (AIS) 中的屏障并提高体细胞树突 tau 蛋白的水平。表达突变 tau 的小鼠模仿乙酰化（KQ）的神经元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 tau 介导的突触可塑性损伤，伴有突触后支架蛋白 KIBRA 缺乏。尽管 AD 大脑中的 KIBRA 减少，提高 KIBRA 表达可防止 KQ 诱导的大鼠神经元中的 LTP 缺陷。我们建议进一步剖析 act-tau 介导的突触可塑性缺陷的潜在机制结合人类神经元和小鼠模型的记忆。在目标 1 中，我们将重点关注 ac-tau 对 AIS，在限制人类体细胞树突区室的轴突蛋白方面发挥着关键作用神经元。我们将使用我们新建立的诱导多能干细胞 (iPSC) 衍生的人类神经元平台和 CRISPR/cas9 基因组编辑来建立表达乙酰模拟 tau 的同基因系内源水平。然后我们将与徐克博士合作，使用随机光学重建显微镜 (STORM) 对人类轴突和树突中的 AIS 结构蛋白和 tau 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 是否能够访问结合使用 STORM 和实时成像来破坏 AIS 的树突棘。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 中，使用光漂白后荧光恢复。然后我们将比较 WT 和 KQ tau 交叉的程度 AIS 并确定专门使用笼状紫杉醇恢复 AIS 屏障功能是否会正常化 tau 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。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 tau 的一个等位基因来引起 tau 介导的突触缺陷 KIBRA 在表达人类野生型 tau 的小鼠中。 KIBRA 的各个域直接与突触后相互作用蛋白质，包括 PICK1、突触足蛋白、树突蛋白、动力蛋白和 PKM z，调节肌动蛋白细胞骨架和/或 AMPAR 贩运。使用包含特定信号传导域的 KIBRA 突变体，我们建议鉴定哪些 KIBRA 介导的信号传导在 tau 介导的突触毒性中发挥着关键作用。通过结合机械对人类 iPSC 衍生神经元的解剖和小鼠模型的体内电路研究，我们期望获得新颖的见解可以转化为对抗 tau 介导的认知衰退的疗法。