Novel Strategies and Mechanisms to Target APOE and Alzheimer's Disease

针对 APOE 和阿尔茨海默病的新策略和机制

• 批准号: 9814735
• 负责人: DAVID M. HOLTZMAN
• 金额: $ 376.01万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9814735
• 关键词: APP-PS1; Abeta clearance; Address; Adult; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Antibodies; Antisense Oligonucleotides; Apolipoprotein E; Attenuated; Automobile Driving; Bacterial Artificial Chromosomes; Binding; Brain; Complex; Data; Disease; Genotype; Grant; Human; In Vitro; Injury; Innate Immune Response; Knock-in Mouse; Knock-out; LDL-Receptor Related Protein 1; Late Onset Alzheimer Disease; Life; Low Density Lipoprotein Receptor; Mediating; Microglia; Modeling; Mus; Nerve Degeneration; Neurons; Pathogenesis; Pathology; Phagocytosis; Protein Isoforms; Proteins; Public Health; Risk; Senile Plaques; Synapses; System; TREM2 gene; Tauopathies; Testing; Therapeutic; Work; abeta accumulation; abeta deposition; apolipoprotein E-2; apolipoprotein E-3; apolipoprotein E-4; beta amyloid pathology; cerebral atrophy; genetic risk factor; improved functioning; in vivo; mouse model; novel; novel strategies; overexpression; prevent; relating to nervous system; tau Proteins; treatment effect; virtual

APOE genotype is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD) with apoE4 increasing risk and apoE2 decreasing risk. In addition to apoE’s strong effects on Aβ clearance and aggregation, it has other effects that are important in how it may influence AD pathogenesis in an isoform- dependent fashion. We found that either lowering apoE or removing apoE/Aβ complexes in APP/PS1- 21;human apoE knockin (KI) mice produces beneficial effects in mouse models of Aβ deposition or tauopathy. Lowering apoE levels with anti-sense oligonucleotides (ASOs) early in life decreased Aβ deposition. When lowered after Aβ seeding had occurred, it did not lower Aβ deposition but it significantly decreased the amount of Aβ-induced neuritic dystrophy. In a mouse model of primary tauopathy (P301S Tau Tg mice), apoE4 markedly increased tau-mediated neurodegeneration, and both brain atrophy and the innate immune response were blocked in P301S mice lacking apoE. The data suggest that apoE is exacerbating the brain’s innate immune response in the setting of neural damage to worsen injury. Recently, we found that Trem2, an apoE receptor on microglia, strongly inhibits Aβ-induced neuritic tau seeding and spreading. To further understand whether targeting apoE should be in some way move forward therapeutically as well as further define whether its effects are Trem2-dependent, we propose to utilize models where 1) we have evidence that apoE is driving tau-mediated neurodegeneration and 2) a model in which Aβ pathology and tau seeding/spreading occur in a fashion that mimics types of Aβ and tau AD pathology seen in human AD. We hypothesize that apoE, in an isoform-dependent fashion, influences Aβ-mediated tau seeding/spreading and tau-mediated neurodegeneration in a TREM2-dependent fashion and that therapeutically reducing apoE levels in the adult CNS will attenuate amyloid-induced damage to neurons, amyloid-induced tau seeding/spreading, and tau-induced neurodegeneration. We propose these aims. Aim 1. To determine whether lowering apoE levels either before or after the onset of tau pathology with ASOs or via over-expression of the low density lipoprotein receptor (LDLR) decreases neurodegeneration, synaptic loss, the innate immune response, and improves function in P301S;apoE KI mice. We will also decrease human TREM2 with ASOs or activate it with agonizing TREM2 antibodies in P301S;apoE KI mice also expressing human TREM2. Aim 2: To determine the effects of targeting apoE by lowering apoE levels either before or after the onset of human AD-tau seeding with ASOs targeting apoE, by administering an antibody to non-lipidated apoE, or via over-expression of LDLR in APPNL-F ;E2, APPNL-F ;E3, and APPNL-F ;E4 mice. Aim 3: We will utilize a mouse neuronal/mixed glial culture system to assess the effects of apoE isoforms on tau-mediated neurodegeneration and determine 1) whether secreted apoE is responsible for the effects on tau-mediated neurodegeneration and 2) whether TREM2 is required for the effects of apoE and is either upstream or downstream of apoE.

载脂蛋白E基因型是晚发性阿尔茨海默病（AD）的最强遗传危险因素，载脂蛋白E4 apoE 2降低风险。除了apoE对Aβ清除的强烈作用外， 聚集，它有其他的影响，这是重要的，它如何可能影响AD发病机制的亚型- 依赖的方式。我们发现降低apoE或去除apoE/Aβ复合物在APP/PS1- 21;人apoE敲入（KI）小鼠在Aβ沉积或tau蛋白病的小鼠模型中产生有益作用。 在生命早期使用反义寡核苷酸（ASO）降低apoE水平可减少Aβ沉积。当 在Aβ接种发生后降低，它不降低Aβ沉积，但显著降低A β沉积量。 Aβ诱导的神经炎性营养不良在原发性tau蛋白病的小鼠模型（P301 S Tau Tg小鼠）中，apoE 4 显著增加tau介导的神经变性，以及脑萎缩和先天免疫反应 在缺乏apoE的P301 S小鼠中被阻断。数据表明，apoE加剧了大脑的先天性 免疫反应在神经损伤的情况下加重损伤。最近，我们发现Trem 2，一个apoE， 受体，强烈抑制Aβ诱导的神经炎性tau的播种和扩散。进一步了解 靶向apoE是否应该以某种方式在治疗上向前推进，以及进一步确定是否 它的影响是Trem 2依赖的，我们建议利用模型，其中1）我们有证据表明，apoE是驱动 tau介导的神经变性和2）Aβ病理学和tau播种/扩散发生在神经变性中的模型。 模拟在人类AD中观察到的Aβ和tau AD病理类型的方式。我们假设apoE，在一个 亚型依赖性方式，影响Aβ介导的tau接种/扩散和tau介导的 在一些实施方案中，本发明涉及以TREM 2依赖性方式抑制神经变性和治疗性降低神经变性中的apoE水平的方法。 成年CNS将减弱淀粉样蛋白诱导的对神经元的损伤，淀粉样蛋白诱导的tau播种/扩散， 和tau诱导的神经变性。我们提出这些目标。目标1。为了确定降低apoE是否 在具有ASO的tau病理学发作之前或之后，或通过低密度 脂蛋白受体（LDLR）减少神经变性、突触丢失、先天免疫应答， 改善P301 S;apoE KI小鼠的功能。我们还将用ASO减少人TREM 2或用ASO激活它。 激动P301 S中的TREM 2抗体;也表达人TREM 2的apoE KI小鼠。目标2：确定 通过在人AD-tau接种开始之前或之后降低apoE水平来靶向apoE的作用 与靶向apoE的ASO，通过给予非脂化apoE的抗体，或通过LDLR的过表达 在APPNL-F ;E2、APPNL-F ;E3和APPNL-F ;E4小鼠中。目的3：我们将利用小鼠神经元/混合胶质细胞培养 系统来评估apoE同种型对tau介导的神经变性的影响，并确定1）是否 分泌的apoE负责对tau介导的神经变性的影响，以及2）TREM 2是否是 是apoE作用所必需的，并且是apoE的上游或下游。

项目成果

Emerging roles of innate and adaptive immunity in Alzheimer's disease.

• DOI: 10.1016/j.immuni.2022.10.016
• 发表时间: 2022-12-13
• 期刊: IMMUNITY
• 影响因子: 32.4
• 作者: Chen, Xiaoying;Holtzman, David M.
• 通讯作者: Holtzman, David M.

Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons.

Tau蛋白病严重破坏了新兴神经动力学的稳态设定点，但不会破坏单个神经元的活动。

• DOI: 10.1101/2023.09.01.555947
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: McGregor,JamesN;Farris,ClaytonA;Ensley,Sahara;Schneider,Aidan;Wang,Chao;Liu,Yuqi;Tu,Jianhong;Elmore,Halla;Ronayne,KeenanD;Wessel,Ralf;Dyer,EvaL;Bhaskaran-Nair,Kiran;Holtzman,DavidM;Hengen,KeithB
• 通讯作者: Hengen,KeithB