Determining the effect of INPP5D/SHIP1 deficiency in neuroinflammation and Alzheimer's disease pathologies

确定 INPP5D/SHIP1 缺陷对神经炎症和阿尔茨海默病病理学的影响

• 批准号: 10728327
• 负责人: Emilie Castranio
• 金额: $ 7.88万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10728327
• 关键词: APP-PS1; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Amyloidosis; Anti-Inflammatory Agents; Behavior; Biochemistry; Biological Assay; Biological Response Modifiers; Brain; Brain Diseases; Brain region; Cause of Death; Cell Surface Receptors; Cells; Cerebrum; Clinic; Cognition; Cognitive deficits; Dementia; Deposition; Disease; Disease Outcome; Elderly; Equilibrium; Evaluation; Event; FRAP1 gene; Genes; Genetic Recombination; Genetic Transcription; Genetic study; Gliosis; Goals; Hematopoietic; Heterogeneity; Immunohistochemistry; Microglia; Modeling; Mus; Myeloid Cells; Nature; Neurodegenerative Disorders; Osteoclasts; Outcome; PIK3CG gene; PP5 protein-serine-threonine phosphatase; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway Analysis; Pathway interactions; Phagocytosis; Phenotype; Population; Proliferating; Receptor Activation; Role; Running; Signal Pathway; Signal Transduction; TREM2 gene; TYROBP gene; Tamoxifen; Tauopathies; Testing; Translating; United States; Up-Regulation; Wild Type Mouse; abeta accumulation; abeta deposition; amyloid pathology; behavioral outcome; drug testing; extracellular; gene network; genetic variant; genome sequencing; genome wide association study; hyperphosphorylated tau; improved; in vivo; inducible Cre; inositol-1,4,5-trisphosphate 5-phosphatase; insight; knock-down; mouse model; multiple omics; neuroinflammation; overexpression; pharmacologic; phosphoinositide-3,4,5-triphosphate; phosphoinositide-3,4-bisphosphate; prevent; response; risk variant; single-cell RNA sequencing; tau Proteins; transcriptomics; whole genome

PROJECT SUMMARY Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with aging and is the most common cause of dementia. In recent years, genetic studies have revealed a number of risk loci in or near genes expressed in microglia, suggesting a key role for microglia in AD pathogenesis. Inositol polyphosphate-5- phosphatase D (INPP5D) is one of the microglia-specific targets converged on by these genetic studies. INPP5D is primarily expressed by cells of the hematopoietic lineage, including microglia, and encodes a 5’ phosphatase protein known as SHIP1. INPP5D/SHIP1 is a negative regulator of immune cell surface receptors, including TREM2/TYROBP, by catalyzing the conversion of PI(3,4,5)P3 to PI(3,4)P2 to prevent receptor activation and downstream signaling, counteracting the PI3K/mTOR pathway. SHIP1 limits microglia functions associated with survival, proliferation and phagocytosis. INPP5D could be an important target for microglia-focused AD therapies, although it is still unknown how decreasing or increasing INPP5D expression affects pathology or behavioral outcomes in vivo. Inhibiting INPP5D expression promotes microglial proliferation, and phagocytosis, each of which is considered to be an important potential cellular phenotype for preventing or reducing AD pathology and improving disease outcomes. The aim of this proposal is to increase our understanding of the function of INPP5D/SHIP1 in the microglial response in diseased brain. We will use Inpp5dflox mice crossed with an inducible CX3CR1-CreER, in which tamoxifen-induced Cre expression results in persistent recombination in long-lived microglia, but not short-lived myeloid cells. For each aim, we will induce microglia-specific knockdown in models representing the pathological hallmarks of AD, Aβ deposition (APPKM670/671NL/PSEN1Δexon9) in Aim 1 and tauopathy (MAPTP301S) in Aim 2. We hypothesize that Inpp5d/SHIP1 deficiency outcomes are driven by TYROBP overexpression/upregulation, i.e. ameliorated pathogenic forms of amyloid pathology and cognitive deficits in amyloid mouse model but exacerbated tau pathology and cognitive deficits in tauopathy model. Importantly, pharmacological targeting both to activate and inhibit SHIP1 are being explored. It is necessary to understand the role of Inpp5d/SHIP1 in diseased brain before further drug testing. It is our hope that with the understanding gained in this proposal, we will be able to appropriately target Inpp5d/SHIP1 for disease and begin the next steps to test these compounds for their efficacy in brain with the intent to translate to the clinic.

项目概要 阿尔茨海默病 (AD) 是一种与衰老相关的进行性神经退行性疾病，是最常见的疾病 痴呆症的常见原因。近年来，遗传学研究揭示了基因内或附近的许多风险位点 在小胶质细胞中表达，表明小胶质细胞在 AD 发病机制中发挥着关键作用。肌醇多磷酸-5- 磷酸酶 D (INPP5D) 是这些遗传学研究集中的小胶质细胞特异性靶标之一。 INPP5D 主要由造血谱系细胞（包括小胶质细胞）表达，并编码 5' 磷酸酶 蛋白质称为 SHIP1。 INPP5D/SHIP1 是免疫细胞表面受体的负调节因子，包括 TREM2/TYROBP，通过催化 PI(3,4,5)P3 转化为 PI(3,4)P2 来防止受体激活和 下游信号传导，抵消 PI3K/mTOR 通路。 SHIP1 限制与以下相关的小胶质细胞功能 生存、增殖和吞噬作用。 INPP5D 可能是针对小胶质细胞的 AD 的重要靶点 疗法，尽管目前尚不清楚减少或增加 INPP5D 表达如何影响病理学或 体内行为结果。抑制 INPP5D 表达促进小胶质细胞增殖和吞噬作用， 每一种都被认为是预防或减少 AD 的重要潜在细胞表型 病理学和改善疾病结果。 该提案的目的是增加我们对 INPP5D/SHIP1 在小胶质细胞中的功能的理解 患病大脑的反应。我们将使用与诱导型 CX3CR1-CreER 杂交的 Inpp5dflox 小鼠，其中 他莫昔芬诱导的 Cre 表达导致长寿命小胶质细胞的持续重组，但不会导致短寿命小胶质细胞的重组 骨髓细胞。对于每个目标，我们将在代表病理学的模型中诱导小胶质细胞特异性敲低 AD 的标志，目标 1 中的 Aβ 沉积 (APPKM670/671NL/PSEN1Δexon9) 和目标 2 中的 tau 蛋白病 (MAPTP301S)。 假设 Inpp5d/SHIP1 缺陷结果是由 TYROBP 过度表达/上调驱动的，即 改善淀粉样蛋白小鼠模型中淀粉样蛋白病理学和认知缺陷的致病形式，但 tau 蛋白病模型中的 tau 蛋白病理学和认知缺陷加剧。重要的是，药理学针对这两者 激活和抑制 SHIP1 的方法正在探索中。有必要了解 Inpp5d/SHIP1 在 在进一步药物测试之前先检查患病的大脑。我们希望，凭借在该提案中获得的理解，我们 将能够适当地针对疾病的 Inpp5d/SHIP1 并开始测试这些化合物的后续步骤 表彰其对大脑的功效，并打算转化为临床。