BHUSSRY SEMINAR SERIES – “Targeting Lipoprotein Lipase in Neurodegenerative Disease”

The Department of Biochemistry and Dean for Research present the 2021-2022 Bhussry Seminar Series.

Kimberley Bruce, Assistant Professor
Division of Endocrinology, Metabolism and Diabetes
University of Colorado Anschutz Medical Campus

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 can protect against or exacerbate AD progression, depending on their composition. For example, the E4 isoform of the major BLp scaffold protein APOE can stabilize amyloid-beta (Aβ), leading to plaque formation and 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.

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 data has shown that increasing LPL activity can enhance microglial phagocytosis of Aβ and lipoprotein uptake, which presents a novel strategy to ameliorate AD progression, particularly in APOE4 carriers. During this presentation we will talk about our published studies detailing the role of LPL in microglial phagocytosis, and immunometabolism and discuss its potential as a therapeutic target for AD and beyond.