Targeting Microglial Lipoprotein Lipase in Alzheimer's disease

点击翻译按钮获取中文摘要

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.