RESUMEN
Depression is one of the most common psychiatric diseases and the prevalence of depressive symptoms in women is almost twice compared to men, although the reasons of this gender difference are not fully understood yet. Recently, soluble amyloid beta (Aß)1-42 peptide has been receiving great importance in the development of depression, also considering that depression is highly comorbid with Alzheimer's disease and other neurodegenerative illnesses. The central role played by Aß in the development of depressive-like symptoms in rodents has been evidenced in environmental rodent model of depression. Indeed, we have previously found that lifelong exposure to n-3 polyunsaturated fatty acids (PUFA) deficient diet in female rats at 8 weeks of life leads to depressive like- symptoms and higher susceptibility to stress associated with increased Aß levels. In order to understand if such effects were maintained over time, rats were exposed to the same diet regimen until 6 or 21 weeks of life. We found that both timepoints of exposure to n-3 PUFA deficient diet lead to depressive-like phenotype. Furthermore, a significant alteration in brain neurochemistry was retrieved. In particular, in hippocampal area a significant reduction in serotonin (5-HT) and noradrenaline (NA) content was evidenced. Considering the prominent role of NA in counterbalancing neuroinflammatory state, we quantified in the same brain area kynurenine levels, a metabolite of tryptophan implicated in inflammatory state and brought to the fore for its implication in depression. Interestingly, kynurenine levels were significantly increased in hippocampus (HIPP) of female rats exposed to such diet. In addition, lifelong deficiency in n-3 PUFA dietary intake led to systemic increase of corticosterone, hence hypothalamic pituitary adrenal (HPA) axis hyperactivation, and higher proinflammatory cytokine production. Increased production of kynurenine, along with HPA axis hyperactivation, have been associated with immune system modulation, particularly through Toll-like receptor type 2 (TLR2) and Toll-like receptor type 4 (TLR4) involvement. In addition, it has been shown that soluble forms of Aß1-42 can induced depressive like-phenotype in consequence to a crosstalk between TLR4 and 5-HTergic system. Thus, considering that in this model we have previously reported increased plasma Aß1-42 level, we quantified TRL2 and 4 expression in HIPP of treated rats. We found that chronic exposure to a diet characterized by very low n-3 PUFA content led to higher expression of TLR2 and TLR4 in HIPP of female treated rats, indicating an activation of the immune system and was accompanied by increased expression of oligomeric Aß. Taken together, our data indicate that the pro-depressive effects induced by a diet poor in n-3 PUFA can be attributable to a shift of hippocampal tryptophan metabolism toward inflammatory metabolite ultimately corresponding to altered immune response and increased Aß oligomerization.
Asunto(s)
Péptidos beta-Amiloides , Ácidos Grasos Omega-3 , Animales , Depresión , Femenino , Sistema Hipotálamo-Hipofisario , Quinurenina , Fenotipo , Sistema Hipófiso-Suprarrenal , Ratas , Receptores Toll-LikeRESUMEN
Depression is one of the most common psychiatric diseases and the prevalence of depressive symptoms in women is almost twice compared to men, although the reasons of this gender difference are not fully understood yet. Recently, soluble Aß1-42 peptide has been receiving great importance in the development of depression, also since depression is highly comorbid with Alzheimer's disease and other neurodegenerative illnesses. Accordingly, we have previously shown that central Aß injection is able to elicit depressive-like phenotype in male rats. In the present study, we reproduced for the first time the Aß-induced depressive-like model in female rats, evaluating behavioural and neurochemical outcomes. Moreover, we studied the effect of lifelong exposure to either n-3 PUFA enriched or n-3 PUFA deficient diet, in female rats, both intact and after central Aß administration. Our results confirmed the Aß-induced depressive-like profile also in female rats. Moreover, chronic exposure to n-3 PUFA deficient diet led to highly negative alterations in behavioural and neurochemical parameters, while lifelong exposure to n-3 PUFA enriched diet was able to restore the Aß-induced depressive-like profile in female rats. In conclusion, the Aß-induced depressive-like profile was reversed by n-3 PUFA supplementation, indicating a possible therapeutic role of n-3 PUFA in the treatment of the burden of depressive disorders.