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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

APOE 基因型是与 apoE4 相关的晚发性阿尔茨海默病 (AD) 的最强遗传风险因素除了 apoE 对 Aβ 清除和降低的强烈影响外，apoE2 还降低了风险。聚集，它还有其他重要作用，对于如何影响亚型 AD 发病机制来说很重要- 我们发现降低 APP/PS1- 中的 apoE 或去除 apoE/Aβ 复合物。 21；人 apoE 敲入 (KI) 小鼠对 Aβ 沉积或 tau 蛋白病的小鼠模型产生有益影响。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。 Aβ 接种发生后降低，它不会降低 Aβ 沉积，但显着减少了数量在原发性 tau 蛋白病小鼠模型（P301S Tau Tg 小鼠）中，apoE4 可以抑制 Aβ 诱导的神经营养不良。 tau 介导的神经变性、脑萎缩和先天免疫反应显着增加在缺乏 apoE 的 P301S 小鼠中被阻断。数据表明 apoE 正在加剧大脑的先天性。最近，我们发现了 Trem2，一种 apoE。小胶质细胞上的受体，强烈抑制 Aβ 诱导的神经炎 tau 播种和扩散。靶向 apoE 是否应该以某种方式在治疗上取得进展，并进一步确定是否它的影响依赖于 Trem2，我们建议使用模型，其中 1) 我们有证据表明 apoE 正在驱动 tau 介导的神经变性和 2) Aβ 病理学和 tau 播种/传播发生在模仿人类 AD 中 Aβ 和 tau AD 病理类型的时尚我们以一种方式对抗 apoE。同种型依赖性方式，影响 Aβ 介导的 tau 播种/扩散和 tau 介导神经退行性变以 TREM2 依赖性方式进行，并且治疗性降低 ApoE 水平成人中枢神经系统将减轻淀粉样蛋白诱导的神经元损伤、淀粉样蛋白诱导的 tau 播种/扩散、我们提出这些目标 1. 确定是否降低 apoE。 ASOs tau 病理发生之前或之后的水平或通过低密度的过度表达脂蛋白受体（LDLR）可减少神经退行性变、突触损失、先天免疫反应和改善 P301S;apoE KI 小鼠的功能我们还将用 ASO 减少人类 TREM2 或用 ASO 激活它。激动 P301S 中的 TREM2 抗体；也表达人 TREM2 的 apoE KI 小鼠目标 2：确定。在人类 AD-tau 接种开始之前或之后通过降低 apoE 水平来靶向 apoE 的效果通过施用非脂化 apoE 抗体或通过 LDLR 过度表达，使用靶向 apoE 的 ASO 在 APPNL-F ;E2、APPNL-F ;E3 和 APPNL-F ;E4 小鼠中目标 3：我们将利用小鼠神经元/混合神经胶质培养物。系统评估 apoE 亚型对 tau 介导的神经变性的影响并确定 1) 是否分泌的 apoE 对 tau 介导的神经变性产生影响，2) TREM2 是否是 apoE 的作用所必需的，并且位于 apoE 的上游或下游。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（2）

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

先天性和适应性免疫在阿尔茨海默病中的新作用。

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：
发表时间：
2023-09-06
期刊：
影响因子：
0
作者：
McGregor JN;Farris CA;Ensley S;Schneider A;Wang C;Liu Y;Tu J;Elmore H;Ronayne KD;Wessel R;Dyer EL;Bhaskaran-Nair K;Holtzman DM;Hengen KB
通讯作者：
Hengen KB