Targeting Microglial Lipoprotein Lipase in Alzheimer's disease

摘要 阿尔茨海默病（AD）是一种毁灭性的、与年龄相关的、最终致命的神经退行性疾病。 虽然AD的患病率在不断增加，但目前还没有有效的治疗方法可以预防或延缓AD的发生 发病 脑源性脂蛋白（BLps）在整个大脑中转运脂质，是一种新兴的靶点， AD治疗。例如，主要BLp支架蛋白APOE的E4同种型可以稳定淀粉样蛋白-APOE。 β-淀粉样蛋白（Aβ），导致斑块形成和AD风险增加。然而，由于BLps的次优隔离， 在早期的研究中，以及使用非脂化的APOE 4，重要的问题尚未得到解答。什么 因子调节BLp加工，它们能靶向治疗AD吗？ 小胶质细胞在BLp加工和AD病理生理学中起主要作用。最近的研究表明 吞噬细胞小胶质细胞通过其脂蛋白脂酶（LPL）的升高表达来定义; 脂蛋白水解和摄取的酶。值得注意的是，表达LPL的小胶质细胞吞噬Aβ，以保护免受 Aβ斑块形成。LPL具有保护作用的观点与流行病学研究一致， 在携带功能获得性LPL的个体中，Aβ斑块形成减少，AD患病率降低 变体。虽然LPL是治疗AD的潜在靶点，但尚未在体内验证。 我的实验室在脂质代谢、LPL生物学和小胶质细胞方面拥有丰富的专业知识， 定位于研究LPL作为AD的治疗靶点。我们之前已经证明LPL调节 小胶质细胞吞噬，脂蛋白摄取和免疫功能，因此确定LPL作为一种 小胶质细胞中免疫代谢看门人（布鲁斯等人，2018; Loving等人，2021年）。此外，我们令人信服的 初步数据显示，增加LPL活性可增强小胶质细胞对Aβ和BLps的摄取。 因此，我们推测，小胶质细胞LPL有助于清除Aβ和多余的BLps，以防止AD 在体内增加LPL活性可以改善AD进展。为了验证这一点，在AIM I，我们将使用小胶质细胞特异性敲除小鼠（MiLPLKD）和AD易感小鼠（5xFAD）来经验性地 确定药理学LPL激活是否可以阻止AD进展。我们还将使用最先进的 代谢成像和`组学方法，以确定LPL依赖的机制控制小胶质细胞 代谢和功能。在AIM II中，我们将使用从人CSF中小心分离的天然BLps来定义LPL-1。 依赖机制管理脂蛋白加工的小胶质细胞，并确定是否增强 LPL活性是恢复APOE 4携带者脂质处理的合理策略。这项研究的结果将是 改变了我们对大脑中脂蛋白处理和导致AD机制的理解 神经发病机制我们的研究不仅将确定LPL依赖的调节小胶质细胞的机制， 但也将确定新的LPL激活剂是否可以改善小胶质细胞的功能， 改善AD病理，这是一种具有重大临床影响的新策略。

ABSTRACT Alzheimer's disease (AD) is a devastating, age-associated, and ultimately fatal neurodegenerative disorder. Although the prevalence of AD is increasing, there are no effective therapies that can prevent or delay AD onset. Brain-derived Lipoproteins (BLps), transport lipids throughout the brain, and are an emerging target for AD therapeutics. For example, the E4 isoform of the major BLp scaffold protein APOE can stabilize amyloid- beta (Aβ), leading to plaque formation and increased AD risk. However, due to the suboptimal isolation of BLps in earlier studies, and the use of unlipidated APOE4, important questions have been left unanswered. What factors regulate BLp processing, and can they be targeted to treat AD? Microglia play a major role in BLp processing and AD pathophysiology. Recent studies have shown that phagocytic microglia are defined by their elevated expression of lipoprotein lipase (LPL); the rate-limiting enzyme in lipoprotein hydrolysis and uptake. Notably, LPL-expressing microglia engulf Aβ to protect against Aβ plaque formation. The notion that LPL is protective is consistent with epidemiological studies showing reduced Aβ plaque formation and decreased AD prevalence in individuals harboring gain-of-function LPL variants. Although LPL is a potential target for the treatment of AD, this has not been validated in vivo. My laboratory has substantial expertise in lipid metabolism, LPL biology, and microglia and is uniquely positioned to investigate LPL as a therapeutic target for AD. We have previously shown that LPL regulates microglial phagocytosis, lipoprotein uptake, and immune function, hence identifying LPL as an immunometabolic gatekeeper in microglia (Bruce et al., 2018; Loving et al., 2021). Furthermore, our compelling preliminary data has shown that increasing LPL activity can enhance microglial uptake of Aβ and BLps. Therefore, we hypothesize that microglial-LPL helps to clear Aβ and excess BLps to protect against AD development and that increasing LPL activity in vivo can ameliorate AD progression. To test this, in AIM I, we will use microglial-specific knockdown mice (MiLPLKD) and AD susceptible mice (5xFAD) to empirically determine whether pharmacological LPL activation can halt AD progression. We will also use state-of-the-art metabolic imaging and `omics approaches to identify LPL-dependent mechanisms controlling microglial metabolism and function. In AIM II, we will use native BLps carefully isolated from human CSF to define LPL- dependent mechanisms governing lipoprotein processing by microglia and to determine whether enhancing LPL activity is a rational strategy to restore lipid handling in APOE4 carriers. The findings from this study will be transformative to our understanding of lipoprotein handling in the brain and the mechanisms leading to AD neuropathogenesis. Our study will not only determine LPL-dependent mechanisms regulating microglial metabolism and function but will also ascertain whether novel LPL activators can improve microglial function to ameliorate AD pathology, a new strategy with major clinical impact.