Targeting IDOL-ApoE receptor pathway in Alzheimer's disease

靶向 IDOL-ApoE 受体通路治疗阿尔茨海默病

• 批准号: 10461318
• 负责人: Jie Gao
• 金额: $ 39.38万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461318
• 关键词: APP-PS1; Abeta clearance; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloidosis; Antisense Oligonucleotides; Apolipoprotein E; Apolipoproteins; Binding; Biology; Brain; Cognitive deficits; Cytoplasmic Tail; Data; Dementia; Development; Disease; Excitatory Synapse; Functional disorder; Genetic; Genotype; Goals; Impaired cognition; In Vitro; Knock-in; Knowledge; LDL-Receptor Related Protein 1; Label; Lipids; Low Density Lipoprotein Receptor; Lysosomes; Mediating; Metabolism; Methods; Microglia; Molecular; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathway interactions; Pharmacology; Play; Proteins; Recycling; Regulation; Research; Risk; Role; Senile Plaques; Signal Transduction; Surface; Synapses; Synaptic plasticity; Testing; Therapeutic; Transgenic Mice; Ubiquitination; VLDL receptor; Validation; age related; apolipoprotein E-4; base; beta amyloid pathology; cell type; cognitive function; combat; density; improved; in vivo; knock-down; mouse model; new therapeutic target; novel; novel strategies; postsynaptic; receptor; response; sex; single-cell RNA sequencing; tau Proteins; therapeutic target; ubiquitin-protein ligase; uptake

Apolipoprotein E (APOE) genotype has long been known to strongly influence the risk and the onset of Alzheimer’s disease(AD), yet the exact mechanisms underlying remain incompletely defined. Accumulating evidence suggested that the functional combination of ApoE and its receptors act together to modify the risk for AD, and targeting brain ApoE receptors has recently emerged as a promising therapeutic strategy to combat AD. However, the lack of knowledge on the endogenous pathways regulating brain ApoE receptors is a major hurdle to advance ApoE receptors as accessible therapeutic targets in AD. Previously, we have identified the inducible degrader of the LDLR (IDOL), an E3 ubiquitin ligase, is a major post-translational regulator of three brain ApoE receptors: low-density lipoprotein receptor (LDLR), very low-density lipoprotein receptor (VLDLR), and ApoE Receptor 2 (ApoER2). Each of these three ApoE receptor plays key role in modulating ApoE actions and impacting AD pathogenesis. Our studies showed the genetic deletion or pharmacological inhibition of IDOL in the brain significantly increase the protein levels of ApoE receptors, ameliorate amyloid-β (Aβ) pathology, and improve cognitive functions in an AD mouse model, suggesting inhibition of brain IDOL activity may serve as a promising therapeutic strategy for AD. For the mechanistic and therapeutic implications, we propose to further investigate the multifactorial role and molecular mechanisms of IDOL-ApoE receptors pathway in modulating ApoE actions and impacting AD pathology. Aim 1 is to characterize the microglia-intrinsic role of IDOL in Aβ pathology. Aim 2 is to elucidate the mechanisms on how IDOL reduction facilitates microglia response to Aβ pathology. Aim 3 is to define the role of neuronal IDOL-ApoER2 pathway in protecting against ApoE4-induced synaptic dysfunction and cognitive deficit in AD.

载脂蛋白E(APOE)基因型别早已被认为强烈影响风险和 阿尔茨海默病(AD)的发病，但其背后的确切机制仍然 定义不完全。越来越多的证据表明，载脂蛋白E的功能结合 和它的受体共同作用，改变AD的风险，靶向大脑ApoE受体 最近出现了一种有希望的治疗策略来对抗阿尔茨海默病。然而，缺乏 对调节大脑载脂蛋白E受体的内源性途径的了解是实现 载脂蛋白E受体作为AD治疗靶点的研究进展 此前，我们已经确定了LDLR(Idol)的可诱导降解物，即E3泛素 连接酶是脑内三种载脂蛋白E受体的主要翻译后调节因子：低密度 脂蛋白受体、极低密度脂蛋白受体和载脂蛋白E受体 2(ApoER2)。这三种载脂蛋白E受体中的每一种都在调节载脂蛋白E的作用和 影响AD发病机制。我们的研究表明基因缺失或药物作用 抑制大脑中的Idol显著增加ApoE受体的蛋白质水平， 改善淀粉样蛋白β(Aβ)病理改变，改善AD模型小鼠的认知功能， 提示抑制脑偶像活动可能是一种有前途的治疗策略 广告。对于机制和治疗的影响，我们建议进一步研究 Idol-ApoE受体通路在调控中的多因素作用及其分子机制 APOE行动和对AD病理的影响。目的1是表征小胶质细胞的内在作用。 β病理中的偶像。目标2是阐明偶像减少如何促进的机制 小胶质细胞对β病理的反应。目标3是定义神经元Idol-ApoER2的作用 抗载脂蛋白E4诱导的AD突触功能障碍和认知功能障碍的途径。