UC San Diego

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.