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

项目总结 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 痴呆症的常见原因。近年来，遗传学研究揭示了一些在基因内或其附近存在的危险基因。 在小胶质细胞中表达，提示小胶质细胞在AD发病机制中起关键作用。肌醇多聚磷酸-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点之一。INPP5D 主要由包括小胶质细胞在内的造血系细胞表达，并编码5‘磷酸酶 被称为SHIP1的蛋白质。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来阻止受体激活和 下游信号，抵消PI3K/mTOR通路。SHIP1限制与小胶质细胞相关的功能 存活、增殖和吞噬。INPP5D可能是小胶质细胞聚集性AD的重要靶点 治疗，尽管目前仍不清楚INPP5D表达的减少或增加如何影响病理或 活体内的行为结果。抑制INPP5D的表达促进小胶质细胞的增殖和吞噬， 其中每一种都被认为是预防或减少AD的重要潜在细胞表型 病理和改善疾病结局。 这项建议的目的是为了加深我们对INPP5D/SHIP1在小胶质细胞中功能的理解 病变脑组织的反应。我们将使用Inpp5dflx小鼠与可诱导的CX3CR1-Creer杂交，其中 他莫昔芬诱导的Cre表达导致长期存活的小胶质细胞持续重组，但不是短暂的 髓系细胞。对于每个目的，我们将在代表病理的模型中诱导小胶质细胞特异性的击倒 AIM 1的AD，Aβ沉积(APPKM670/671NL/PSEN1Δ外显子9)和AIM 2的互变(MAPTP 301S)。 假设INPP5D/SHIP1缺陷的结果是由TYROBP过度表达/上调驱动的，即 改善淀粉样变性小鼠模型的致病形式和认知功能障碍 加重tau病模型的病理和认知功能障碍。重要的是，药物靶向 激活和抑制SHIP1的作用正在探索中。有必要了解INPP5D/SHIP1在 在进一步的药物测试之前，他的大脑已经患病。我们希望，随着在这项建议中获得的理解，我们 将能够适当地针对疾病的INPP5D/SHIP1，并开始下一步测试这些化合物 它们在大脑中的功效，意在转化到临床上。

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.