Background: Lipid dyshomeostasis and inflammation co-aggregate as common features in neurodegenerative diseases including tauopathies. Emerging evidence suggests an intertwined relationship between lipid metabolic processes and type-I interferon (IFN-I) inflammation, indicating that intervening in either of these processes can modulate the pathogenesis of neurodegenerative conditions. However, the relationship between lipid metabolism, IFN-I inflammation in the context of tau-mediated neurodegenerative processes remains unclear. This project aims to investigate the relationship between lipid metabolic processes, IFN-I inflammation in the pathogenesis of tau proteinopathy.

Methods: SH-SY5Y cells stably expressing tau-WT or disease-associated tau-mutants (P301L, P301S, V337M, K369I, R406W) were assessed for disease-associated phosphorylation of tau and IFN-I inflammation via western blot analysis. Fluorescent imaging was performed to assess lipid droplet (LD) formation and analysed via Imaris. 100 µM of oleic acid was introduced to induce LD formation. 5-month age-matched WT-mice and transgenic mice harbouring human-tau-K369I (K3 mice) were assessed for LD formation via fluorescent imaging.

Key findings: Increased p-tau-S262 and PHF-13 were consistently observed in tau-mutant cells harbouring mutation within microtubule binding domain. Interestingly, LD formation was consistently reduced in tau-mutant cells, a phenotype that is associated with elevated IFN-I inflammation (p-TBK1 and p-STAT1) which ameliorated when LD was reconstituted with oleic acid. Importantly, reduced LD formation was recapitulated in K3 mice. 

Conclusions: Reduced LD formation may reflect altered lipid metabolic processes. Interestingly, induced LD formation ameliorated IFN-I inflammation suggesting the interplay relationship between lipid metabolism and IFN-I inflammation. Further investigation is warranted to understand how tau abnormalities mechanistically lead to lipid metabolic disturbances.