Astrocytic HIF-1a as a therapeutic target for Alzheimer's-like comorbidity of HAND

星形胶质细胞 HIF-1a 作为手部阿尔茨海默病样合并症的治疗靶点

• 批准号: 10161502
• 负责人: Susmita Sil
• 金额: $ 42.09万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161502
• 关键词: Alzheimer like pathology; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Amyloidosis; Anxiety; Astrocytes; Atomic Force Microscopy; Behavior; Brain; Brain region; CD34 gene; Cells; Cleaved cell; Cognitive deficits; Complex; Dendritic Spines; Dependence; Development; Doxycycline; Endosomes; Endothelial Cells; Engineering; Enzymes; Exclusion; Exposure to; Extracellular Space; Future; Gene Silencing; Genetic Transcription; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Hippocampus (Brain); Human; Impaired cognition; In Vitro; Individual; Infection; Injury; Lead; Longevity; Macaca; Mediating; Membrane; Memory; Motor Activity; Multivesicular Body; Mus; Neuraxis; Neuroglia; Neuronal Dysfunction; Neuronal Injury; Neurons; Pathology; Pathway interactions; Patients; Peptides; Play; Prevalence; Process; Proteins; Proteomics; Regimen; Reporting; Rodent Model; Role; SIV; Sampling; Senile Plaques; Severities; Site; Small Interfering RNA; Synapses; Techniques; Testing; Therapeutic; Therapeutic Intervention; Thinking; Thinness; Tissues; Trans-Activators; Transgenic Organisms; Transmission Electron Microscopy; Ultracentrifugation; Validation; Viral; Viral Proteins; Virus Replication; Western Blotting; Work; abeta deposition; age related; antiretroviral therapy; base; beta-site APP cleaving enzyme 1; cell type; cognitive function; comorbidity; conditioned fear; cytotoxic; efficacy testing; exposed human population; extracellular; extracellular vesicles; functional outcomes; humanized mouse; hypoxia inducible factor 1; in vitro Model; in vivo; innovation; interest; mouse model; nervous system disorder; neuropathology; neurotoxic; neurotoxicity; novel; therapeutic RNA; therapeutic development; therapeutic target; uptake

Abstract Although the lifespan of individuals living with HIV-1 has increased significantly owing to effective combination anti- retroviral therapy (cART), paradoxically however, in almost 50% of infected individuals there is increased prevalence of HIV-1-associated neurocognitive disorders (HAND), which remains an important comorbidity. It is suggested that persistence of cytotoxic viral protein such as HIV-1 Tat that accumulates despite cART, could likely contribute to this process. Additionally, reports on Alzheimer’s like pathology in patients with HAND are also extant, likely attributable to the action of both HIV-1 infection and the cytotoxic viral Tat protein in neurons and endothelial cells. A recent study from our lab has shown that HIV-1 Tat could also induce amyloidosis in yet another cell type, the astrocytes, via the HIF-1α-BACE1-antisense (AS) pathway in an in vitro model. Validation of these findings was also demonstrated in the brains of SIV-infected macaques & HIV-infected patients’ samples, and this amyloids could be an important contributing factor to neurotoxicity associated with HAND. Based on our recent report that astrocytes can produce amyloids following exposure to Tat, we hypothesized that the toxic amyloid forms secreted by Tat-stimulated astrocytes in the astrocyte-derived extracellular vesicles (ADEVs) could be taken up by the neuorns, resulting in exacerbated neuronal injury. The concept of uptake by neurons of astrocyte released amyloids via the ADEVs is a novel idea and has never been explored before. In this exploratory R21 proposal, we will test the hypothesis in two aims: Aim 1: a) Determine how HIF-1α regulates HIV-1 Tat-mediated release of ADEVs carrying neurotoxic amyloids (Aβ 1-42) cargoes which, in turn, can be taken up by the neurons, leading to synaptodendritic injury, and Aim 2: b) Determine how the delivery of HIF-1A siRNA via the ADEV cargoes can inhibit amyloidosis and the associated cognitive decline in two relevant rodent models of HAND- inducible transgenic Tat mice model as well as the humanized mice model of HIV infection. These findings could have ramifications for future development of adjunctive therapeutic interventions targeting astrocytic HIF-1α for treatment of neurological disorders in HIV patients on cART therapy.

摘要 虽然艾滋病毒1型感染者的寿命由于有效的抗- 然而，矛盾的是，逆转录病毒治疗（cART）在几乎50%的感染者中的流行率增加 HIV-1相关的神经认知障碍（HAND）仍然是一种重要的合并症。建议在 尽管有cART，细胞毒性病毒蛋白（如HIV-1达特）的持续蓄积可能对此有贡献 过程此外，关于HAND患者的阿尔茨海默病样病理学的报告也存在，这可能是由于 HIV-1感染和细胞毒性病毒达特蛋白在神经元和内皮细胞中的作用。最近的一项研究 来自我们实验室的研究表明，HIV-1达特还可以通过免疫抑制剂诱导另一种细胞类型星形胶质细胞的淀粉样变性。 体外模型中的HIF-1α-BACE 1-反义（AS）通路。这些发现的有效性也得到了证实， SIV感染猕猴的大脑和HIV感染患者的样本，这种淀粉样蛋白可能是重要的 与HAND相关的神经毒性的促成因素。根据我们最近的报告，星形胶质细胞可以产生 淀粉样蛋白暴露于达特后，我们假设毒性淀粉样蛋白形式分泌的塔特刺激， 星形胶质细胞衍生的细胞外囊泡（ADEV）中的星形胶质细胞可以被神经元摄取，导致 加重了神经元损伤。神经元通过ADEV摄取星形胶质细胞释放的淀粉样蛋白的概念是一个新的概念。 这是一个新的想法，以前从未被探索过。在这个探索性的R21建议中，我们将在两个方面测试这个假设。 目的：目的1：a）确定HIF-1α如何调节HIV-1 Tat介导的携带神经毒性淀粉样蛋白的ADEV释放 （Aβ 1-42）货物，反过来，可以采取的神经元，导致突触树突损伤，和目的2：B） 确定HIF-1A siRNA通过ADEV货物的递送如何抑制淀粉样变性和相关的炎症反应。 在两种相关的啮齿动物模型的HAND-诱导的转基因达特小鼠模型以及 HIV感染的人源化小鼠模型。这些发现可能会对未来的发展产生影响。 以星形胶质细胞HIF-1α为靶点的治疗性干预用于治疗接受cART的HIV患者的神经系统疾病 疗法

项目成果

Mitochondrial Extracellular Vesicles in CNS Disorders: New Frontiers in Understanding the Neurological Disorders of the Brain.

• DOI: 10.3389/fmolb.2022.840364
• 发表时间: 2022
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5