RESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Ácidos Grasos Omega-3/fisiología , Ácidos Grasos Omega-6/fisiología , Esfingolípidos/fisiología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Animales , Sistema Nervioso Central/metabolismo , Ceramidas/antagonistas & inhibidores , Ceramidas/fisiología , Modelos Animales de Enfermedad , Ácidos Grasos Insaturados/metabolismo , Predicción , Humanos , Inflamación , Lipooxigenasas/metabolismo , Lisofosfolípidos/fisiología , Ratones , Microglía/patología , Modelos Biológicos , Prostaglandina-Endoperóxido Sintasas/metabolismo , Receptores de Reconocimiento de Patrones/fisiología , Esfingosina/análogos & derivados , Esfingosina/fisiología , Moduladores de los Receptores de fosfatos y esfingosina 1/uso terapéuticoRESUMEN
Chronic inflammation is known to promote the development of many chronic diseases. Pattern recognition receptors (PRRs), Toll-like receptors (TLRs), and nucleotide-binding oligomerization domain proteins (NODs) mediate both infection-induced inflammation and sterile inflammation by recognizing pathogen- associated molecular patterns and endogenous molecules, respectively. PRR-mediated inflammation is an important determinant in altering the risk of many chronic diseases. Saturated fatty acids (SFAs) can activate PRRs, leading to enhanced expression of pro-inflammatory target gene products. However, n-3 polyunsaturated fatty acids (PUFAs) inhibit agonist-induced activation of PRRs. These results suggest that SFAs and n-3 PUFAs can reciprocally modulate PRR-mediated inflammation, and that PRRs and their downstream signaling components are molecular targets for dietary strategies to reduce chronic inflammation and subsequent risk of chronic diseases. This advancement in knowledge provides a new paradigm for understanding the mechanism by which different dietary fatty acids modify risk of chronic diseases including insulin resistance, atherosclerosis, and cancer.