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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2024)

Dysregulation of lipid metabolism is implicated in neurodegenerative diseases like Alzheimer's disease (AD). Lipid droplets (LDs) are dynamic organelles essential for cellular lipid metabolism and homeostasis. Investigating the interplay between LDs and AD pathology offers insights into disease mechanisms and therapeutic avenues. Here, we studied LD accumulation in tauopathy brains, utilizing stimulated Raman scattering imaging to visualize LD distribution in fly and mouse models of tauopathy, iPSC-neurons and a microglia cell line. . LD accumulation in the brain was accompanied by increased expression of lipogenesis genes and LD-associated proteins. Remarkably, LD accumulation was predominantly found in activated microglia, suggesting an interplay between tauopathy neurons and microglia. Activation of neuronal AMPK reduced LD accumulation and neuroinflammation in vitro and in vivo. Our findings elucidate the intricate link between AMPK, LD biology, and tau pathology, offering insights into therapeutic strategies for neurodegenerative diseases. On the other hand, we investigated the effects of β-hydroxybutyrate (BHB), a ketone body produced by fat metabolism implicated in neuroprotection, using a fly model of tauopathy and a microglia cell line BHB supplementation ameliorated tauopathy phenotypes in flies and reduced LD accumulation in microglia, primarily through the signaling activity of BHB. Together, our results suggest that targeting lipid metabolism could be a potential therapeutic intervention for tauopathies and neuroinflammation.

    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2023)
    Studies have shown that brain lipid metabolism is associated with biological aging and influenced by dietary and genetic manipulations; however, the underlying mechanisms are elusive. High-resolution imaging techniques propose a novel and potent approach to understanding lipid metabolic dynamics in situ. Applying deuterium water (D2O) probing with stimulated Raman scattering (DO-SRS) microscopy, we revealed that lipid metabolic activity in Drosophila brain decreased with aging in a sex-dependent manner. Female flies showed an earlier occurrence of lipid turnover decrease than males. Dietary restriction (DR) and downregulation of insulin/IGF-1 signaling (IIS) pathway, two scenarios for lifespan extension, led to significant enhancements of brain lipid turnover in old flies. Combining SRS imaging with deuterated bioorthogonal probes (deuterated glucose and deuterated acetate), we discovered that, under DR treatment and downregulation of IIS pathway, brain metabolism shifted to use acetate as a major carbon source for lipid synthesis. For the first time, our study directly visualizes and quantifies spatiotemporal alterations of lipid turnover in Drosophila brain at the single organelle (lipid droplet) level. Our study not only demonstrates a new approach for studying brain lipid metabolic activity in situ but also illuminates the interconnection of aging, dietary, and genetic manipulations on brain lipid metabolic regulation.
      Cover page: Bioorthogonal Stimulated Raman Scattering Imaging Uncovers Lipid Metabolic Dynamics in Drosophila Brain During Aging
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