Alzheimer’s disease (AD) is the most common form of dementia, with late-onset AD (LOAD) accounting for approximately 95% of all cases. Evidence from genome-wide association and epidemiological studies has implicated disrupted lipid homeostasis in the progression of LOAD^1,2. Lipid droplets are dynamic organelles which store neutral lipids to regulate lipid metabolism and energy homeostasis. Dysfunctional lipid droplet production, dynamics and composition may contribute to AD pathology, with alterations in microglial lipid droplets observed in response to amyloid accumulation³. Although they have been implicated in contributing to neurodegeneration, the precise mechanistic relationship between AD pathology and disrupted lipid droplet biology is not yet fully understood.

We have used the fruit fly Drosophila melanogaster to explore the relationship between glial lipid droplets and AD pathology. Drosophila are a powerful invertebrate model for studying AD, with numerous conserved LOAD-associated genes and well-defined neurodegenerative phenotypes. Importantly, their nervous system is complex, containing neuron and glial subtypes with orthologous functions to mammalian counterparts and well conserved lipid droplet-associated cellular mechanisms. We aimed to investigate how specific AD-associated genes contribute to dysfunctional glial lipid droplet biology, and conversely, how altered glial lipid droplet dynamics influence neurodegenerative pathology.

Previous Drosophila research has elucidated fundamental aspects of glial lipid droplet biology, including a neuroprotective mechanism whereby glial cells uptake peroxidated neuronal lipids and sequester them within lipid droplets⁴. Building on this work, through confocal imaging of a nerve in the adult Drosophila wing, our innovative approach allowed us to investigate changes in glial lipid droplet dynamics in response to i) genetic changes and ii) Wallerian degeneration of neurons. By using restricted expression of genetically encoded fluorescent markers, we were able to quantify changes in the size and abundance of glial lipid droplets. This rapid, medium-throughput approach allowed us to screen lipid droplet phenotypes associated with dozens of AD and lipid associated genes (n = 40, groups containing male and female flies). Using this system, we have made proof of principle measurements demonstrating that disruption of key lipid droplet machinery, including knockdown of Drosophila genes such as Seipin (BSCL2) and Lsd-2 (PLIN2), cause perturbed lipid droplet phenotypes. We are currently investigating how manipulating AD risk gene expression, and neuronal expression of amyloid, impacts on glial lipid droplet dynamics.

In ongoing work, we will test how the mechanisms identified in our invertebrate study contribute to human iPSC-derived glia lipid droplet associated phenotypes. We anticipate our study will provide mechanistic insights into the contribution of dysfunction glial lipid droplet biology to AD, which could inform the identification of novel therapeutic targets.