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

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（由申请人提供）：ApoE 4基因型是发生AD的最强遗传风险因素。然而，ApoE 4基因型和AD之间的这种联系的机制还不清楚。目的/假设：本研究的目的是了解脑磷脂稳态中ApoE 4基因型特异性变化与ApoE 4易感性增加之间相关性的分子基础。我们的初步数据表明，如果与ApoE 3对应物相比，ApoE 4携带者的死后人脑组织、ApoE 4纯合敲入（KI）小鼠的脑和表达ApoE 4等位基因的原代神经元中PI（4，5）P2的水平降低。使PI（4，5）P2去磷酸化降低其水平的synaptojanin 1（synj 1）的表达在ApoE 4脑中升高。我们最近的观察表明，synj 1减少（随后PI（4，5）P2水平升高）可以加速A的内体/溶酶体降解，并改善AD转基因小鼠的认知缺陷。在这项提案中，我们正在测试的假设，即ApoE基因型是脑磷脂稳态的关键决定因素，ApoE 4亚型在这一过程中功能失调（synj 1表达增加，PIP 2水平降低）。因此，ApoE 4通过内体/溶酶体降解途径损害A β learance，加速认知能力下降，并破坏突触功能。这些ApoE 4诱导的异常分子事件级联变化导致长期神经退行性过程和AD发展。原理/实验设计：在本申请中，我们将研究减少synj 1从而使脑磷脂代谢正常化是否可以通过利用具有人ApoE 4或E3纯合KI背景的synj 1单倍不足小鼠模型来挽救ApoE 4相关的神经病理学变化，以评估：1）AD相关的认知功能障碍（aim 1.1）; 2）AD相关的生化变化，如A β清除和ApoE分泌（aim 1.2和1.3）; 3）AD相关的形态学变化和突触磷脂稳态（aim 2）; 4）Synj 1表达/PIP 2稳态中ApoE亚型特异性变化的分子机制（目的3）。相关性/影响：本申请中提出的研究将是第一个将脑磷脂稳态中ApoE 4基因型特异性变化与ApoE 4易感性增加联系起来的机制研究。这些研究可能揭示针对ApoE 4致病性的AD治疗的新的治疗选择。