Tissue-specific modulation of Apolipoprotein E in neurodegeneration

载脂蛋白 E 在神经变性中的组织特异性调节

• 批准号: 10020164
• 负责人: Chantal Ferguson
• 金额: $ 3.05万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2023-09-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020164
• 关键词: Acetylgalactosamine; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapy; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Animal Behavior; Apolipoprotein E; Atherosclerosis; Behavior; Biological; Birth; Brain; Cellular biology; Characteristics; Chemicals; Chemistry; Cholesterol; Clinical; Data; Development; Disease; Disease Progression; Environmental Risk Factor; Etiology; Future; Genes; Genetic; Gliosis; Goals; Health; Healthcare Systems; Hepatic; High Density Lipoproteins; Homeostasis; Human; Impaired cognition; Individual; Injections; Knock-out; Knockout Mice; Lead; Learning; Lipids; Liver; Measures; Memory; Messenger RNA; Modeling; Motor; Motor Neurons; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurologic; Neurons; Outcome Measure; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Plant Roots; Plasma; Production; Protein Isoforms; Provider; RNA Interference; Risk Factors; Serum; Site; Small Interfering RNA; Small RNA; Spinal Cord; Symptoms; Technology; Therapeutic; Tissues; Transgenic Organisms; Treatment Efficacy; Wild Type Mouse; Work; abeta deposition; age related neurodegeneration; clinical efficacy; design; efficacy testing; experience; improved; in vivo; innovation; lipid transport; mouse model; neuron loss; neuropathology; novel; presenilin-1; subcutaneous; superoxide dismutase 1; symptom management; therapeutic development; therapeutic target

PROJECT SUMMARY: Alzheimer’s Disease (AD) and Amyotrophic Lateral Sclerosis (ALS) are multifaceted, progressive neurodegenerative conditions that place a monumental burden on patients, providers, and the public healthcare system. No disease-modifying treatments are currently available for either AD or ALS. Although the etiology of each disease is well studied, strategies targeting characteristic features of disease pathogenesis— e.g., beta-amyloid in AD—show limited clinical efficacy. Identification of novel targets that modify progression of neurodegeneration is needed for innovative therapeutic development across neurodegenerative disorders. AD and ALS are caused by genetic and environmental factors that alter downstream pathways like lipid homeostasis. A critical player in systemic and central nervous system (CNS) lipid transport, that is also implicated in the onset and progression of neurodegeneration, is apolipoprotein E (ApoE). Genetic deletion of ApoE reduces neuropathology in mice, but also causes atherosclerosis. Thus, despite its implication in disease, the diverse functionality of ApoE in its distinct biological “pools” (i.e. systemic and CNS) makes it a challenging therapeutic target. Reducing individual ApoE pools may circumvent this issue. However, the independent effects of systemic or CNS ApoE silencing on neurodegenerative diseases are unclear. The goal of this proposal is to determine the relationship between systemic and CNS ApoE pools, and their effects on disease progression in AD and ALS mice. The project will take advantage of chemically-stable, self- delivering small interfering RNAs (siRNAs) that enable sustained, tissue-specific silencing of target mRNA. GalNAc-siRNAs specifically deliver to liver (site of systemic ApoE production), and divalent (Di)-siRNAs deliver throughout the brain and spinal cord after intra-cerebroventricular (ICV) injection. With guidance from Drs. Anastasia Khvorova (siRNA chemistry), Robert Brown (ALS), Evgeny Rogaev (AD models), Andrew Tapper (animal behavior), and Thomas Smith (neuropathologist), GalNAc- and Di-siRNA will be used to silence hepatic and CNS ApoE, respectively, and the effects on CNS and systemic ApoE pools, and AD and ALS phenotypes, will be examined. In Aim 1, GalNAc-siRNA targeting ApoE will be subcutaneously injected into mice. In Aim 2, Di-siRNA targeting ApoE will be delivered to the CNS via ICV injection. Both aims will utilize the APP/PSEN1 mouse model of AD and the SOD1G93A mouse model of ALS, and will measure systemic and CNS ApoE and cholesterol levels, and AD and ALS neuropathology and behavior two months post injection. These studies will advance the understanding of how ApoE pools interact in the context of neurodegeneration, and the effects on disease progression. Such findings will inform strategies for safe and effective therapeutic targeting of ApoE in AD, ALS, and age-related neurodegenerative disorders.

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