Resolution of inflammation as a therapeutic target for Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, clinically manifested by memory impairment, loss of ability in conducting daily activity and increased need for care, thus causing immense suffering for the afflicted and relatives, as well as a huge economic burden to the society. Despite the existence of symptom-relieving drugs, there is no drug that can stop the progression or cure the disease. Therefore, new disease-modifying drugs are called for. Epidemiological studies suggest that among persons with long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) there is a lower prevalence of AD, and there is extensive evidence for the presence of a chronic inflammation in AD, that may promote pathology and pathogenesis, presenting inflammation as a therapeutic target. Resolution of inflammation belongs to the last phase of the inflammatory response, where inflammation is down-regulated and return to homeostasis is promoted. Chronic inflammation can thus be a result of a failure in resolution mechanisms. The levels of specialized pro-resolving lipid mediators (SPMs), mediators of resolution derived from polyunsaturated fatty acids (PUFA), are decreased in chronic inflammatory diseases including AD, opening a new field of therapeutic intervention for AD by stimulating resolution of inflammation. In Paper I, studies on a human microglial cell line showed that both the omega-3 (n-3) FAs docosahexaenoic (DHA) and eicosapentaenoic acid (EPA), increased microglial phagocytosis of β-amyloid 1-42 (Aβ42) peptide, and down-regulated the pro-inflammatory phenotype. In Paper II, we asked the question how Aβ42 affects the resolution of inflammation. We showed that Aβ42 is more suppressive on the resolution pathway in the human microglia compared to the inflammation induced by lipopolysaccharide (LPS), indicating that there is an impairment of resolution specific for this major molecular pathological hallmark of AD. Paper III describes lower levels of the SPMs maresin 1 (MaR1), protectin D1 (PD1) and resolvin (Rv) D5 in the entorhinal cortex in AD. Also, lipoxin A4 (LXA4), MaR1, RvD1 and protectin DX (PDX) exerted neuroprotective activity against staurosporine-induced apoptosis. MaR1 and RvD1 down-regulated Aβ42-induced pro-inflammatory activation in human microglia. Microglial phagocytosis of Aβ42 was increased by MaR1. Findings in Paper IV on the influence of apolipoprotein (Apo) E4 allele on the plasma SPM levels upon n-3 FA supplementation in AD patients, indicate that conversion of FAs to SPMs is not increased by supplementation with n-3 FAs, and showed that the proportion of patients with unchanged/improved cognition was higher in the n-3 FAtreated group compare to placebo, but only in ApoE4 non-carriers. In conclusion, these studies show that resolution of inflammation is impaired in AD, and support the idea that stimulating the resolution of inflammation is a potential therapeutic strategy in AD.

List of scientific papers

I. Erik Hjorth*, Mingqin Zhu*, Veronica Cortés-Toro, Inger Vedin, Jan Palmblad, Tommy Cederholm, Yvonne Freund-Levi, Gerd Faxen-Irving, Lars-Olof Wahlund, Hans Basun, Maria Eriksdotter & Marianne Schultzberg. Omega-3 fatty acids enhance phagocytosis of Alzheimer's disease-related amyloid-β42 by human microglia and decrease inflammatory markers. J Alzheimers Dis. 35, 697-713.
https://doi.org/10.3233/JAD-130131.

II. Mingqin Zhu, Xiuzhe Wang, Marianne Schultzberg & Erik Hjorth. Differential regulation of resolution in inflammation induced by Aβ42 and lipopolysaccharides in human microglia. J Alzheimers Dis. 43, 1237-1250.
https://doi.org/10.3233/JAD-141233

III. Mingqin Zhu, Xiuzhe Wang, Erik Hjorth, Romain A. Colas, Lisa Schröder, Ann-Charlotte Granholm, Charles N. Serhan & Marianne Schultzberg. Pro-resolving lipid mediators improve neuronal survival and increase Aβ42 phagocytosis. [Manuscript]

IV. Mingqin Zhu, Erik Hjorth, Veronica Cortés-Toro, Yvonne Freund-Levi, Maria Eriksdotter, Jan Palmblad, Tommy Cederholm, Marianne Schultzberg and the OmegAD Study Group. Lipid mediators in plasma from AD patients receiving supplementation with n-3 fatty acids - relation to ApoE4. The OmegAD study. [Manuscript]