Grant: Operating Grant: Joint Programme on Neurodegenerative Disease Research (JPND)

Finding suitable and easily measurable early biomarkers for neurodegeneration and cognitive dysfunctions represents the next frontier for prevention and early intervention strategies. A key may rely on identifying very early environmental risk factors and understanding the temporal and causal relationships between the central alterations and peripheral changes. As part of these early factors, neuroinflammation has been increasingly acknowledged as an important player in Alzheimer's Disease (AD) pathology and early-life adversity primes microglia rendering them more sensitive to subsequent challenges. In addition, polyunsaturated fatty acids (PUFAs) and their derivatives play a key role in modulating microglia. Importantly, these PUFA can be modified by the diet. We thus propose a translational project on neuroimmunology, lipid mediators and metabolic sensors that will leverage human data and biosamples as well as established mouse and rat models to identify early biomarkers of neurodegeneration. Candidates generated in human cohorts will be to back-translate into validated animal models of cognitive decline. We will use several innovative approaches including microglial functional assays, microglia depletion, PUFA/SPM assessment, organotypic slice cultures, and animal models of early-life adversity, AD, omega-3 fatty acid deficiency and microglial defects. On completion of this proposal, we will have identified i) early biomarkers (PUFA/SPM and metabolic sensors) predictive of cognitive dysfunction and neurodegeneration ii) the causal role of early-life adversity on central neuroinflammatory and peripheral alterations associated with neurodegeneration; and iii) a PUFA/SPM dietary intervention strategy for alleviating these effects.