Resolution of inflammation in Alzheimer’s disease

Inflammation is associated with Alzheimer’s disease (AD), a neurodegenerative disorder with no cure up to date. Ample evidence from studies within various disciplines support that inflammation plays a role in AD. Resolution of inflammation is the end stage of inflammation, where the detrimental effects of inflammation are terminated and tissue healing is initiated. Cutting-edge research has demonstrated that resolution of inflammation is controlled by specialized pro-resolving lipid mediators (SPMs). There is emerging evidence for a role of SPMs in various diseases associated with inflammation. One of the SPMs, neuroprotectin D1 (NPD1) was the first to be found in reduced levels in the brain of AD patients. The aims of this thesis were to investigate the resolution status in AD, the mechanisms therein, and the therapeutic potential. In Paper I, we aimed to answer the fundamental question, whether and how the resolution pathway is altered in AD patients. To this end, we analysed cerebrospinal fluid (CSF) and postmortem samples from AD and non-AD patients. We found that in the CSF and hippocampus of AD patients, the levels of one of the SPMs, lipoxin A4, LXA4 were lower than that in non-AD groups. This was further confirmed by analysis of a smaller number of hippocampal samples with liquid chromatography - tandem mass spectrometry (LC-MS-MS) technique, which also revealed that another SPM, maresin 1 (MaR1) was reduced in AD hippocampus. Furthermore, the CSF levels of LXA4, as well as resolvin D1 (RvD1), were positively correlated to mini mental statement examination (MMSE) scores. The cellular distribution of two SPM receptors, LXA4 receptor/formyl peptide receptor 2 (ALX/FPR2) and chemerin receptor 23 (ChemR23) were also described in the human brain. We then investigated if the abnormal resolution may play a role in the pathogenesis of AD. For this purpose, in Paper II, we used a senescence-accelerated mouse model, SAMP8 mice, to study the balance between inflammation and resolution during an abnormal aging progress, since the primary risk of AD is aging. We found that inflammation in SAMP8 mice increased with age, and was higher than that in age-matched control mice. However, the resolution markers LXA4 and RvD1 remained unchanged upon age in SAMP8 mice, or equal to the levels in control mice. Thus, SAMP8 mice appeared to have an unresponsive resolution during the abnormal aging. We also found that enzymes involved in the synthesis of SPMs were abnormally regulated during aging in SAMP8 mice, and that this was related to amyloid β (Aβ) and tau pathology. In Paper III, we analysed materials from a double-blind, randomized, placebo-controlled clinical trial, where n-3 fatty acids or placebo were orally supplemented to AD patients for 6 months. Peripheral blood mononuclear cells (PBMCs) were obtained before and after the trial, and incubated with Aβ ex vivo. We found that there was reduced production of LXA4 and RvD1 by the Aβ-exposed PBMCs in the placebo group, and that n-3 fatty acid supplementation prevented this reduction. There was a positive correlation between altered levels of plasma transthyretin, and the SPMs released from the PBMCs. Finally, in Paper IV, we investigated the therapeutic potential of a resolution stimulating strategy. Using LC-MS-MS technique, we were able to study a broad range of lipid mediators, and found that MaR1 is also reduced in the entorhinal cortex of AD patients. MaR1, as well as LXA4, RvD1, and NPD1 showed direct neuroprotective effects against staurosporine-induced cell death in vitro, and MaR1 specifically exerted phenotypemodulation effects on human microglial cells, and promoted the phagocytosis of Aβ. In conclusion, we have demonstrated that the resolution pathway is altered in AD, and has a relationship with disease development and pathology. Novel therapeutic strategies based on stimulating resolution should be further investigated