Toxicity mechanisms of Aβ42 and Tau in aged cells

Aβ42 和 Tau 在衰老细胞中的毒性机制

• 批准号: 10469528
• 负责人: Chuankai Zhou
• 金额: $ 19.4万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469528
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Behavioral; Biological Aging; Biological Assay; Biological Process; CRISPR screen; Cell Culture Techniques; Cell model; Cells; Chemicals; Clinical; Clinical Trials; Cognitive deficits; Confocal Microscopy; Defect; Dementia; Deposition; Development; Disease; Disease Progression; Drosophila melanogaster; Failure; Functional disorder; Genetic; Goals; Grant; Health Benefit; Human; Intervention; Late Onset Alzheimer Disease; Left; Link; Longevity; Mammalian Cell; Methodology; Methods; Microscopic; Mitochondria; Modeling; Molecular; Neurons; Older Population; Patients; Pattern; Peptides; Persons; Physiology; Pilot Projects; Predisposition; Process; Proteins; Proteome; Research; Resistance; Resolution; Role; Saccharomyces cerevisiae; Structure; System; Tauopathies; Testing; Toxic effect; Work; Yeast Model System; Yeasts; abeta accumulation; abeta toxicity; age related; age related neurodegeneration; aged; cell age; cell type; cytotoxicity; design; fly; healthspan; hyperphosphorylated tau; insight; mitochondrial dysfunction; neuron loss; neurotoxic; normal aging; novel; novel strategies; overexpression; prevent; programs; protein expression; proteostasis; repaired; screening; successful intervention; tau Proteins

ABSTRACT Alzheimer's disease (AD) is characterized by a progressive loss of neuronal structures and functions that underlie cognitive defects and dementia. The neuronal damage has been linked to the aggregation of Aβ peptides and hyperphosphorylated Tau proteins. However, clinical results of reducing these neurotoxic proteins have been disappointing. These failures suggest that AD is a multifactorial process and that many cellular defects were left uncorrected after removing the Aβ/Tau depositions. Finding these resistant cellular defects is a critical step towards the successful intervention of AD. Studies in humans have shown that aging is the biggest risk factor for AD. However, most cellular mechanisms of Aβ/Tau toxicity are generated by research in young cells. As aged cells have different proteomes and physiology than young cells, studying the cellular toxicity of Aβ42/Tau in aged cells is a better model for their toxicity in older AD patients and is required to reveal the resistant cellular defects that are induced by Aβ42/Tau during aging. The goal of this proposal is to determine how Aβ/Tau, together with aging, changes the cellular compartmentalization and whether rejuvenating some of these defects can protect cells from the toxicity of Aβ/Tau. Identifying these age-specific Aβ/Tau sensitive targets will reveal novel mechanisms of Aβ/Tau toxicity and enable strategies to rescue cellular defects that are left uncorrected after removing the Aβ/Tau depositions. We propose to use Saccharomyces cerevisiae (yeast) and Drosophila melanogaster (fly) for this pilot project as these two model organisms are widely used to study molecular mechanisms of aging and AD. Yeast and fly share many biological processes with humans and develop age- related cellular dysfunctions similar to human aging. The yeast model of AD has been used to reveal conserved mechanisms of amyloid aggregation and the cellular toxicity of Aβ and Tau, as well as the genetic and chemical toxicity modifiers. However, these studies looked at the young yeast cells expressing the human Aβ/Tau proteins. Therefore, we want to combine the strength of aging and AD research in yeast to screen for the defects of protein expression and localization caused by Aβ42/Tau in aged cells. Our strategy is to use aged yeast to screen for hits and test the conserved ones in fly models of AD. We intend to accomplish our goal by 1) determining how Aβ and Tau proteins interfere with protein expression and localization in replicatively old yeast cells, and 2) evaluating the beneficial effect of newly identified longevity factors in fly models of AD. The yeast screen will be accomplished by using a new high-throughput microscopic screening method developed in our lab for aged cells. The insights gained from the yeast screen will also be tested in the fly models of AD. This work will advance our understanding of the interactions between aging and AD-related proteins that together cause the age-related neurodegenerative diseases.

摘要 阿尔茨海默病（AD）的特征在于神经元结构和功能的进行性丧失， 是认知缺陷和痴呆症的基础神经元损伤与Aβ聚集有关 肽和过度磷酸化的Tau蛋白。然而，减少这些神经毒性蛋白质的临床结果 都令人失望这些失败表明AD是一个多因素的过程，许多细胞缺陷 在去除Aβ/Tau沉积物后未校正。找到这些抵抗性细胞缺陷是一个关键 向成功干预AD迈出了一步。对人类的研究表明，衰老是最大的风险 AD的因素。然而，大多数Aβ/Tau毒性的细胞机制是通过对年轻细胞的研究产生的。 由于衰老细胞具有与年轻细胞不同的蛋白质组和生理学，研究Aβ42/Tau的细胞毒性 在老年细胞中是其在老年AD患者中毒性的更好模型，并且需要揭示耐药细胞 在老化过程中由Aβ42/Tau诱导的缺陷。该提案的目标是确定Aβ/Tau， 与衰老一起，改变了细胞的区室化， 能保护细胞免受Aβ/Tau的毒性。识别这些年龄特异性Aβ/Tau敏感靶点将揭示 Aβ/Tau毒性的新机制，并使策略能够挽救未纠正的细胞缺陷 在去除Aβ/Tau沉积物之后。我们建议使用酿酒酵母（酵母）和果蝇 由于这两种模式生物被广泛用于研究分子生物学， 衰老和AD的机制。酵母和苍蝇与人类有许多共同的生物学过程， 类似于人类衰老的细胞功能障碍。AD的酵母模型已被用于揭示保守的 淀粉样蛋白聚集的机制和Aβ和Tau的细胞毒性，以及A β和Tau的遗传和化学作用。 毒性调节剂然而，这些研究着眼于表达人类Aβ/Tau蛋白的年轻酵母细胞。 因此，我们希望联合收割机结合酵母老化和AD研究的力量，筛选蛋白质的缺陷 Aβ42/Tau在衰老细胞中的表达和定位。我们的策略是使用老化的酵母来筛选 并在AD的果蝇模型中检测保守的基因。我们打算通过以下方式实现我们的目标：1）确定如何 Aβ和Tau蛋白干扰复制老化酵母细胞中的蛋白表达和定位，以及2） 评估新鉴定的长寿因子在AD的果蝇模型中的有益作用。酵母筛选将是 通过使用我们实验室开发的用于老化细胞的新的高通量显微镜筛选方法来完成。 从酵母筛选中获得的见解也将在AD的苍蝇模型中进行测试。这项工作将促进我们的 了解衰老和AD相关蛋白质之间的相互作用，这些蛋白质共同导致与年龄相关的疾病 神经退行性疾病

项目成果

Tom70-based transcriptional regulation of mitochondrial biogenesis and aging.

• DOI: 10.7554/elife.75658
• 发表时间: 2022-03-02
• 期刊: eLife
• 影响因子: 7.7
• 作者: Liu Q;Chang CE;Wooldredge AC;Fong B;Kennedy BK;Zhou C
• 通讯作者: Zhou C

Nascent mitochondrial proteins initiate the localized condensation of cytosolic protein aggregates on the mitochondrial surface.

• DOI: 10.1073/pnas.2300475120
• 发表时间: 2023-08
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Liu, Qingqing;Fong, Benjamin;Yoo, Seungmin;Unruh, Jay R.;Guo, Fengli;Yu, Zulin;Chen, Jingjing;Si, Kausik;Li, Rong;Zhou, Chuankai
• 通讯作者: Zhou, Chuankai