BRAIN · Bioactive lipids Regulate Adaptive Immune responses in Neurodegeneration: novel target for treatment?

Traditionally, AD is regarded as a neurodegenerative disease and as such, the major focus has been on investigating and treating neurodegeneration and neuronal functioning. Only the last decade, it became apparent that AD pathogenesis strongly interferes with immunological processes and vice versa. Indeed, my novel findings show that the immune system in patients with early AD is already severely derailed and highlight a specific role for CD8+ T-cells. My exciting data also suggest the importance of bio-active lipids like sphingolipids and specialized pro-resolving mediators in early AD pathogenesis, possibly by controlling the immune system. The identification of how the altered lipid landscape underlies AD and affects immune homeostasis is essential to come to new insights into disease pathogenesis and to discover novel intervention strategies, the ultimate goal of the BRAIN project. I therefore here hypothesize that a misbalance in bioactive lipids plays a key role in the induction and propagation of the impaired immune homeostasis associated with AD progression, thereby forming a novel target for treatment. My key objectives are:i) Unravel bioactive lipid signatures and define correlations with disease progression, sex, biomarkers and an unbalanced immune response in early AD, ii) Elucidate the underlying mechanisms of uncontrolled lipid mediator balance and how this relates to the altered immune landscape, iii) Identify key players in this process and perform proof of concept studies to define if restoring the lipid balance reinstates immune homeostasis and consequently cognition and disease pathogenesis in AD.Together this study will provide in-depth understanding of how bio-active lipids affect immune mediated processes that underlie disease progression, investigate interaction thereof and decode underlying mechanisms to pave the way towards the development of improved prognostic/diagnostic tools and identification of novel therapeutic targets.