Abstract
Alzheimer’s disease (AD) is the leading cause of dementia worldwide giving rise to devastating forms of cognitive decline, which impacts patients’ lives and that of their proxies. Pathologically, AD is characterized by extracellular amyloid deposition, neurofibrillary tangles and chronic neuroinflammation. To date, there is no cure that prevents progression of AD. In this review, we elaborate on how bioactive lipids, including sphingolipids (SL) and specialized pro-resolving lipid mediators (SPM), affect ongoing neuroinflammatory processes during AD and how we may exploit them for the development of new biomarker panels and/or therapies. In particular, we here describe how SPM and SL metabolism, ranging from ω-3/6 polyunsaturated fatty acids and their metabolites to ceramides and sphingosine-1-phosphate, initiates pro- and anti-inflammatory signaling cascades in the central nervous system (CNS) and what changes occur therein during AD pathology. Finally, we discuss novel therapeutic approaches to resolve chronic neuroinflammation in AD by modulating the SPM and SL pathways.
Highlights
The central nervous system (CNS) is one of the most important but vulnerable parts of the human body
The APOE genotype was not found to have a significant influence on the SL levels. These findings suggest that age is an important factor regarding SL metabolism, where increased S1P levels might play a role in the early development of Alzheimer’s disease (AD) and, as observed in post-mortem AD brains, these levels decrease over time
It became clear that both SL and specialized pro-resolving lipid mediators (SPM) metabolism are major players in the onset and resolution of excessive neuroinflammation during AD
Summary
The central nervous system (CNS) is one of the most important but vulnerable parts of the human body. CNS-specific cell types, for example microglia, oligodendrocytes, and astrocytes, play a vital role in securing CNS homeostasis and supporting neuronal functioning. The BBB consists of endothelial cells, which are supported by pericytes and astrocytes, together regulating the flow of molecules and cells in and out of the CNS to safeguard its homeostasis [1,2,3,4,5]. Despite years of research and increasing fundamental knowledge, only a few treatments have been developed and used, but none of such interventions results in curing these devastating neurodegenerative diseases, thereby creating a high and unmet clinical need. More fundamental insight into pathological mechanisms that underlie AD pathology is needed to facilitate the development of potential novel treatment regimes. Frontiers in Immunology | www.frontiersin.org de Wit et al
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