Sphingosine 1-phosphate (S1P) system in healthy brain and alzheimer's disease

Abstract

The physiological consequences of the super-specialization of the lipids in the different regions and cellular types of the central nervous system (CNS), remain largely being a mystery. In fact, the so-called neurolipids, which possess agonistic or neuromodulatory properties, play an essential role both in health and in pathological conditions. Thus, the lysophospholipid sphingosine 1-phosphate (S1P) system is one of these neurolipids involved in immune responses and cell survival functions. However, the S1P systems in CNS is not fully elucidated.Then, the present research study evaluates the S1P system in healthy brain and AD. In this sense, the anatomical distribution of functional coupling of G'i/o proteins to S1P1 receptor in postmortem human brain samples and rodent models showed that S1P1 receptor could be one of the most abundant and/or efficient GPCR coupled to Gii/o proteins in the brain and consequently signaling and regulating multiple biological processes. Moreover, the present results, indicate that is preferably the use of rat models to the study of S1P1 receptors activity in human neurodegenerative diseases, such as Alzheimer¿s disease.The S1P1 receptor activity during the AD progression in postmortem human brain samples indicated that the S1P1 receptor signaling was decreased in superficial layers of the frontal cortex during the initial stages. In contrast, the activities of both S1P1 and CB1 receptors, were increased at the initial stages of the disease in the internal layers of the frontal cortex that could be related to neuroprotection. Furthermore, the activity of the S1P1 receptor in the underlying cortical white matter was increased during the initial and intermediate stages of the disease. Finally, the activities of both, S1P1 and CB1 receptors, were reduced in the hippocampus at the most severe stages of the disease indicating the continuation of the brain impairment.Lipidomic evaluation of human plasma samples from mild cognitive impairment (MCI) and AD patients to identify biomarkers for early diagnosis. To sum up, the MCI patients showed a decrease in some lipid species such as TG in general, PC and PE containing linoleic acid, and some Cer. In contrast, the AD patients showed increase in some PE compared to MCI patients, but other lipid species, such as PC and SM, were decreased. Moreover, the changes in AD patients respect to control patients were mainly focused on Cer, SM and PC.The functionality of S1P1 receptors in the CNS of 3xTg-AD mice model of familial AD showed a decrease in some areas of the olfactory bulb, in the nucleus basalis magnocellularis, basolateral amygdaloid nucleus, fimbria and molecular layer of the hippocampal dentate gyrus, the substantia nigra and in the ventral tegmental area. All this changes could be related to the learning and memory impairment and the fear and anxiety behavior in this model. On the other hand, the activity of the S1P1 receptor in the CNS of sporadic AD by cholinergic basalocortical lesion showed an increase in the basolateral amygdaloid nucleus and the piriform cortex in layers I and II that could be related to the rearrangement at the projection areas. Conversely, a decrease was observed in the nucleus basalis magnocellularis and the corpus callosum associated to the apoptotic processes that follow the injury in this area.The analysis of the relationship between the S1P and cannabinoid systems indicated a possible crosstalk of both systems. S1P1 'selective' compounds have also certain affinity for CB1 receptors and the S1P1 activity is regulated after in vivo cannabinoid treatments, indicating a crosslink between S1P and eCB systems.The MALDI-IMS technique allows us to obtain extensive information for the field of lipidomics, demonstrating the relevance of the super-specialization of lipids in the different regions of the CNS. Moreover, the 'Lipotype' of the different cells that are present in the brain, such as neurons, astrocytes, microglia, oligodendrocytes or ependymocytes, allows us to associate the functions performed by each of these cells with the lipids that compose them. Additionally, the implementation of new techniques of matrix deposition, allows to increase the power of this technique by obtaining the distribution of signaling molecules such as S1P or 2-AG, or even other molecules that otherwise could not be identified.In summary, the S1P system represents a promising target since is related to important physiological functions that in pathological situations may be disturbed, offering an opportunity to modify the progression of such pathologies that include the Alzheimer's disease.