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：
10153606
负责人：
Li Gan
金额：
$ 50.64万
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 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153606
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 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 therapeutically effective 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 蛋白病理学或脑脊液 tau 蛋白相关。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。指出异常乙酰化 tau (ac-tau) 物种的重要致病作用，其水平在 NFT 的升高与 AD 中的认知障碍有关，这是 tau 介导的毒性的关键触发因素。 AD 中的体细胞树突 tau 蛋白升高，我们发现 K274 和 K281 上的 tau 蛋白乙酰化会破坏 Tau 蛋白的稳定性。轴突起始段 (AIS) 中的屏障并提高表达突变 tau 的小鼠体细胞树突 tau 的水平。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。 tau 介导的突触可塑性损伤与突触后支架蛋白 KIBRA 缺乏有关。 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在目标 1 中，我们将重点关注 act-tau 对记忆的影响。 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 的同基因系然后我们将与徐科博士合作并使用随机光学重建。显微镜 (STORM) 对人类轴突和树突中的 AIS 结构蛋白和 tau 分布进行成像在目标 2 中，我们将直接确定 ac-tau 是否能够访问单分子分辨率的神经元。在人类 iPSC 中，结合使用 STORM 和实时成像来破坏 AIS 的树突棘。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在目标 3 中，我们将剖析 tau 介导的突触的突触后机制。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 介导的突触缺陷表达人类野生型 tau 蛋白的小鼠中的 KIBRA 的各个结构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。我们建议使用包含特定信号传导域的 KIBRA 突变体来识别哪些突变体。 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。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。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nav1.1-Overexpressing Interneuron Transplants Restore Brain Rhythms and Cognition in a Mouse Model of Alzheimer's Disease.

Nav1.1 过度表达的中间神经元移植可恢复阿尔茨海默病小鼠模型的脑节律和认知。

DOI：
发表时间：
2018
期刊：
影响因子：
16.2
作者：
Martinez;Tracy, Tara E;Ma, Keran;Verret, Laure;Clemente;Khan, Abdullah S;Cobos, Inma;Ho, Kaitlyn;Gan, Li;Mucke, Lennart;Alvarez;Palop, Jorge J
通讯作者：
Palop, Jorge J

Regulation of Tau Homeostasis and Toxicity by Acetylation.

乙酰化对 Tau 稳态和毒性的调节。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Tracy, Tara;Claiborn, Kathryn C;Gan, Li
通讯作者：
Gan, Li

A MAC2-positive progenitor-like microglial population is resistant to CSF1R inhibition in adult mouse brain.

在成年小鼠大脑中，MAC2 阳性祖细胞样小胶质细胞群对 CSF1R 抑制具有抵抗力。

DOI：
发表时间：
2020
期刊：
影响因子：
7.7
作者：
Zhan, Lihong;Fan, Li;Kodama, Lay;Sohn, Peter Dongmin;Wong, Man Ying;Mousa, Gergey Alzaem;Zhou, Yungui;Li, Yaqiao;Gan, Li
通讯作者：
Gan, Li

New insights and therapeutic opportunities for progranulin-deficient frontotemporal dementia.

颗粒体蛋白前体缺乏性额颞叶痴呆的新见解和治疗机会。

DOI：
发表时间：
2022
期刊：
影响因子：
5.7
作者：
Amin, Sadaf;Carling, Gillian;Gan, Li
通讯作者：
Gan, Li

Discovery of small molecules that normalize the transcriptome and enhance cysteine cathepsin activity in progranulin-deficient microglia.

发现了使颗粒体蛋白前体缺陷的小胶质细胞转录组正常化并增强半胱氨酸组织蛋白酶活性的小分子。

DOI：
发表时间：
2020
期刊：
影响因子：
4.6
作者：
Telpoukhovskaia, Maria A;Liu, Kai;Sayed, Faten A;Etchegaray, Jon Iker;Xie, Min;Zhan, Lihong;Li, Yaqiao;Zhou, Yungui;Le, David;Bahr, Ben A;Bogyo, Matthew;Ding, Sheng;Gan, Li
通讯作者：
Gan, Li