Resolving inflammation : analysis of mechanisms in relation to Alzheimer pathology and aging

Alzheimer’s disease (AD) is the most common type of dementia, and its clinical symptoms are the reflections of pathological changes in the brain. The main pathological features of AD are intracellular aggregates of hyper-phosphorylated tau protein and extracellular deposits of amyloid β (Aβ) peptide in amyloid plaques. Chronic inflammation in the central nervous system (CNS) appears as a crucial hallmark of AD. The excessive presence of Aβ causes a chronic inflammatory response as an outcome of protective host response, and inflammation drives production of Aβ. In return, inflammatory cytokines induce Aβ peptide formation resulting in a vicious circle. Resolution of inflammation has been revealed as an end phase of inflammation for restoring and healing tissue. This process is mediated by pro-resolving lipid mediators (LMs) that are derived from omega-3 and omega-6 essential fatty acids.

Previous studies reported reduced levels of pro-resolving LMs in human CSF and brain of AD patients. Many studies demonstrated the beneficial effects of the bioactive pro-resolving LMs in in vitro and in vivo models for chronic inflammatory diseases. Thus, detailed analysis of the inflammatory and pro-resolving LM production, their synthetic enzymes and receptors is necessary for using these potent LMs as treatment strategy at the appropriate disease stage for AD.

The current studies focused on markers involved in the resolution process and their association to Alzheimer pathology. We showed that receptors activated by pro-resolving LMs and mediating resolution were increased in post mortem human AD brains, indicating compensation for low levels of pro-resolving LMs (Paper I). In the second study, we investigated the changes in the levels of LMs, phospholipids, free fatty acids and inflammatory proteins at different ages in an AD mouse model in order to pinpoint the disruption occurring in the resolution process during disease progression. This study revealed that alterations in the resolution of inflammation could be observed when the Aβ burden was dominant, i.e. at older ages. However, changes in phospholipids in terms of membrane composition occurred earlier in the AD mice compared to wild-type (WT) mice (Paper II). This study led us to test pro-resolving LMs for therapeutic purposes in Paper III. We treated mice with AD pathology by intranasal administration of pro-resolving LMs and performed behavioral tests, electrophysiology and biochemical experiments. We found that pro-resolving LMs recovered both memory and gamma oscillation impairments, as well as decreased neuroinflammation. Based on these results, the molecular and cellular mechanisms affected upon LM treatment can be utilized for a treatment approach in clinical studies.

In conclusion, alterations observed in the synthesis of pro-resolving LMs may occur with healthy aging and at the later stages of disease pathology as shown with human and mouse brains with AD pathology. Pro-resolving LMs can rescue memory impairments by Aβ peptide pathology.

List of scientific papers

I. Ceren Emre, Erik Hjorth, Krishna Bharani, Steven Carroll, Ann-Charlotte Granholm, Marianne Schultzberg. Receptors for pro-resolving mediators are increased in Alzheimer's disease brain. Brain Pathology. 2020; 30(3):614-640.
https://doi.org/10.1111/bpa.12812

II. Ceren Emre, Khanh V. Do, Bokkyoo Jun, Erik Hjorth, Silvia Gómez Alcalde, Marie-Audrey I. Kautzmann, William C. Gordon, Per Nilsson, Nicolas G. Bazan, Marianne Schultzberg. Age-related changes in brain phospholipids and bioactive lipids in the App knockin mouse model of Alzheimer’s disease. Acta Neuropathologica Communications. 2021; 9(1):116.
https://doi.org/10.1186/s40478-021-01216-4

III. Ceren Emre, Luis Arroyo-Garcia, Khanh V. Do, Bokkyoo Jun, Silvia Gómez Alcalde, Silvia Maioli, Per Nilsson, Erik Hjorth, André Fisahn, Nicolas G. Bazan, Marianne Schultzberg. Intranasal delivery of pro-resolving lipid mediators rescued memory and gamma oscillation impairment in App KI mice. [Manuscript]