Characterization of ApoE4 Induced Phospholipid Dysregulation in AD Pathogenesis

AD 发病机制中 ApoE4 诱导的磷脂失调的特征

• 批准号: 9086179
• 负责人: Dongming Cai
• 金额: $ 34万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9086179
• 关键词: AD transgenic mice; Age Factors; Aging; Alleles; Alzheimer' s Disease; Animal Model; Apolipoprotein E; Autopsy; Biochemical; Brain; Cells; Cognitive deficits; Data; Degradation Pathway; Development; Down Syndrome; Event; Experimental Designs; Functional disorder; Future; Gender; Genotype; Health; Hippocampus (Brain); Homeostasis; Human; Impaired cognition; Knock-in; Knock-in Mouse; Laboratories; Lasers; Late Onset Alzheimer Disease; Lead; Learning; Link; Literature; Measures; Membrane; Memory; Metabolism; MicroRNAs; Microfluidics; Microscope; Molecular; Molecular Profiling; Mus; Nature; Nerve Degeneration; Neurites; Neurons; Pathogenesis; Pathway interactions; Patients; Phosphatidylinositol 4,5-Diphosphate; Phospholipid Metabolism; Phospholipids; Phosphoric Monoester Hydrolases; Play; Post-Transcriptional Regulation; Predisposition; Presynaptic Terminals; Process; Protein Isoforms; Research; Role; Slice; Structure; Synapses; Synaptosomes; Techniques; Testing; Up-Regulation; Vertebral column; apolipoprotein E-3; apolipoprotein E-4; behavior test; brain tissue; design; genetic risk factor; hippocampal morphometry; improved; knock-down; mRNA Stability; mouse model; neocortical; novel therapeutics; overexpression; small hairpin RNA; synaptic function; synaptojanin; AD transgenic mice; Age Factors; Aging; Alleles; Alzheimer' s Disease; Animal Model; Apolipoprotein E; Autopsy; Biochemical; Brain; Cells; Cognitive deficits; Data; Degradation Pathway; Development; Down Syndrome; Event; Experimental Designs; Functional disorder; Future; Gender; Genotype; Health; Hippocampus (Brain); Homeostasis; Human; Impaired cognition; Knock-in; Knock-in Mouse; Laboratories; Lasers; Late Onset Alzheimer Disease; Lead; Learning; Link; Literature; Measures; Membrane; Memory; Metabolism; MicroRNAs; Microfluidics; Microscope; Molecular; Molecular Profiling; Mus; Nature; Nerve Degeneration; Neurites; Neurons; Pathogenesis; Pathway interactions; Patients; Phosphatidylinositol 4,5-Diphosphate; Phospholipid Metabolism; Phospholipids; Phosphoric Monoester Hydrolases; Play; Post-Transcriptional Regulation; Predisposition; Presynaptic Terminals; Process; Protein Isoforms; Research; Role; Slice; Structure; Synapses; Synaptosomes; Techniques; Testing; Up-Regulation; Vertebral column; apolipoprotein E-3; apolipoprotein E-4; behavior test; brain tissue; design; genetic risk factor; hippocampal morphometry; improved; knock-down; mRNA Stability; mouse model; neocortical; novel therapeutics; overexpression; small hairpin RNA; synaptic function; synaptojanin

DESCRIPTION (provided by applicant): The ApoE4 genotype is the strongest genetic risk factor for developing AD. However, the mechanisms that underlie this link between ApoE4 genotype and AD are not well understood. Objective/Hypothesis: the objectives of this proposal are to understand the molecular underpinnings of the association between ApoE4 genotype-specific changes in brain phospholipid homeostasis and ApoE4 increased susceptibility to develop late-onset AD. Our preliminary data indicate that the levels of PI(4,5)P2 are reduced in postmortem human brain tissues of ApoE4 carriers, in the brain of ApoE4 homozygous knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles, if compared to ApoE3 counterparts. The expression of synaptojanin 1 (synj1) that dephosphorylates PI(4,5)P2 reducing its levels, is elevated in ApoE4 brains. Our recent observations demonstrate that synj1 reduction (with subsequent elevation of PI(4,5)P2 levels) can accelerate endosomal/lysosomal degradation of A�nd ameliorate cognitive deficits in AD transgenic mice. In this proposal we are testing the hypothesis that ApoE genotype is a critical determinant of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process (increased synj1 expression and reduced PIP2 levels). As a consequence, ApoE4 impairs A�learance through endosomal/lysosomal degradation pathway, accelerates cognitive decline, and disrupts synaptic functions. These ApoE4-induced changes in the cascade of aberrant molecular events lead to long-term neurodegenerative process and AD development. Rationale/Experimental Design: In this application, we will study whether reducing synj1 thus normalizing brain phospholipid metabolism can rescue ApoE4-related neuropathological changes by utilizing mouse models of synj1 haploinsufficiency with human ApoE4 or E3 homozygous KI background in studies that assess: 1) AD-related cognitive dysfunction (aim 1.1); 2) AD-related biochemical changes such as A�learance and ApoE secretion (aim 1.2 and 1.3); 3) AD related morphological changes and synaptic phospholipid homeostasis (aim 2); 4) molecular mechanisms underlying ApoE isoform specific changes in synj1 expression/PIP2 homeostasis (aim 3). Relevance/Impact: The proposed studies in this application will be the first mechanistic studies that link ApoE4 genotype-specific changes in brain phospholipid homeostasis to ApoE4 increased susceptibility to develop AD. These studies may uncover new therapeutic options for the treatment of AD targeting at ApoE4 pathogenic nature.

描述（由应用程序提供）：APOE4基因型是开发AD的强大遗传风险因素。但是，尚不清楚APOE4基因型和AD之间这种联系的基础的机制。目的/假设：该提案的目标是了解APOE4基因型特异性变化与脑磷脂稳态的特异性变化与APOE4之间的关联的分子基础，这增加了开发晚期AD的敏感性。我们的初步数据表明，与APOE3相比，在APOE4载体后载体的PI（4,5）P2的水平降低了APOE4载体的后体人脑组织，APOE4纯合敲入（KI）小鼠的大脑以及表达APOE4等位基因的原发性神经元中的PI（4,5）P2水平。在APOE4大脑中，降低Pi（4,5）p2降低Pi（4,5）p2降低Pi（4,5）的突触janin 1（Synj1）的表达升高。我们最近的观察结果表明，Synj1降低（随后PI（4,5）P2水平的升高）可以加速AD转基因小鼠中AD'ND改善认知缺陷的内体/溶酶体降解。在此提案中，我们正在检验以下假设：APOE基因型是脑磷脂稳态的关键决定剂，并且在此过程中APOE4同工型（Synj1表达增加和PIP2水平降低）在此过程中功能失调。结果，APOE4通过内体/溶酶体降解途径损害了现实术，可以加速认知能力下降，并破坏突触功能。这些APOE4诱导的异常分子事件级联变化导致了长期神经退行性过程和AD发育。 Rationale/Experimental Design: In this application, we will study whether reducing synj1 thus normalizing brain phospholipid metabolism can rescue ApoE4-related neuropathological changes by utilizing mouse models of synj1 haploinsufficiency with human ApoE4 or E3 homozygous KI background in studies that assess: 1) AD-related cognitive dysfunction (aim 1.1); 2）与广告相关的生化变化，例如校准和apoe Secret（AIM 1.2和1.3）； 3）AD相关的形态变化和合成磷脂稳态（AIM 2）； 4）APOE同工型的分子机制在Synj1表达/PIP2稳态中的特定变化（AIM 3）。相关性/影响：本应用程序中提出的研究将是第一个机械研究，将APOE4基因型特异性变化与APOE4联系起来，使脑磷脂稳态的变化增加了增加AD的易感性。这些研究可能会发现用于治疗APOE4致病性的AD靶向的新治疗选择。