Molecular detail of resolution of inflammation in Alzheimer’s disease to develop novel treatment

Sustained microglial activation and increased pro-inflammatory signalling cause chronic inflammation and neuronal damage in Alzheimer’s disease (AD).A novel hypothesis is that the resolution (end stage) of inflammation is dysfunctional in AD and that this is a viable treatment target.We have shown that the resolution of inflammation is dysfunctional and that treatment with specialized pro-resolving lipid mediators (SPMs) reduces memory impairment and neuroinflammation in a mouse AD model.

The purpose is to understand the mechanisms of SPMs on neurons and glia and to identify target molecules for SPMs, with the goal to develop a new effective treatment for AD based on stimulating pro-resolving activities.

We will also analyse whether beneficial effects of SPMs are influenced by the APOE genotype, i.e. is pro-resolving treatment preferential in certain patient groups.Year 1-3: An in vitro assay platform based on human induced pluripotent stem cells (hiPSCs) will be used in high through-put proteome screening and validation of targets, and for mechanistic studies and effects of APOE genotype.

Year 4: The AppNL-G-F/NL-G-F) mouse AD model is used for in vivo validation.The rationale in this project is original and novel in that it emphasizes stimulation of natural transition of the inflammation in the AD-brain from a chronic and harmful state to its beneficial end stage of healing.