Depressive-like phenotype evoked by lifelong nutritional omega-3 deficiency in female rats: Crosstalk among kynurenine, Toll-like receptors and amyloid beta oligomers. Morgese Maria Grazia,Schiavone Stefania,Maffione Angela Bruna,Tucci Paolo,Trabace Luigia Brain, behavior, and immunity 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 (Aβ) 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 Aβ 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 Aβ 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 Aβ 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 Aβ 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 Aβ. 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 Aβ oligomerization. 10.1016/j.bbi.2020.01.015

Sub-chronic celecoxib prevents soluble beta amyloid-induced depressive-like behaviour in rats. Morgese M G,Schiavone S,Bove M,Mhillaj E,Tucci P,Trabace L Journal of affective disorders BACKGROUND:Depression and Alzheimer's disease (AD) are co-morbid conditions. Neuropsychiatric symptoms have been reported as prodromal symptoms of AD-like dementia and soluble forms of beta amyloid peptide (Aβ), the main constituent of insoluble plaques typical of AD brains, have been implicated in such an effect. We have previously shown that intracerebral injection of Aβ can evoke a depressive-like state in rats, accompanied by neurochemical and neuroendocrine alterations reminiscent of depressive symptoms in humans. AD and depression are crucially linked by neuroinflammation and cyclooxygenase II (COX-2) enzyme involvement is an intriguing field of research. Indeed, its pharmacological inhibition has shown both antidepressant and Aβ modulating effects. METHODS:Male rats were exposed to sub-chronic celecoxib (15 mg/kg/day sc for 8 days), a selective COX-2 inhibitor or vehicle (saline), starting from the day before central intracerebroventricular injection of Aβ peptide (5µL of 4 µM solution or vehicle for sham). Animals were tested for depressive-like behaviour by using the forced swimming test paradigm and prefrontal serotonin (5-HT) content and plasma Aβ levels were further evaluated. RESULTS:We found that celecoxib treatment prevented the pro-depressive effects induced by Aβ. Moreover, it also prevented the reduction in 5-HT content in prefrontal cortex of Aβ-treated rats and decreased their plasma Aβ levels. CONCLUSIONS:Taken together, our data indicate that celecoxib could be a suitable pharmaceutical tool for the treatment of depressive state related to increased Aβ levels. 10.1016/j.jad.2018.05.030

Minocycline prevents the development of depression-like behavior and hippocampal inflammation in a rat model of Alzheimer's disease. Amani Mohammad,Shokouhi Ghaffar,Salari Ali-Akbar Psychopharmacology RATIONALE:Considerable clinical and experimental studies have shown that depression-related disorders are the most common neuropsychiatric symptoms in Alzheimer's disease (AD), affecting as many as 20-40% of patients. An increasing amount of evidence shows that monoamine-based antidepressant treatments are not completely effective for depression treatment in patients with dementia. Minocycline, a second-generation tetracycline antibiotic, has been gaining research and clinical attention for the treatment of different neuropsychiatric disorders, and more recently depression symptom in humans. METHODS:In the present study, we investigated the effects of Aβ1-42 administration alone or in combination with minocycline treatment on depression-like behaviors and anti/pro-inflammatory cytokines such as interleukin(IL)-10, IL-β, and tumor necrosis factor (TNF)-α in the hippocampus of rats. RESULTS:Our results showed that Aβ1-42 administration increased depression-related behaviors in sucrose preference test, tail suspension test, novelty-suppressed feeding test, and forced swim test. We also found significant increases in IL-1β and TNF-α levels in the hippocampus of Aβ1-42-treated rats. Interestingly, minocycline treatment significantly reversed depression-related behaviors and the levels of hippocampal cytokines in Aβ1-42-treated rats. CONCLUSION:These findings support the idea that there is a significant relationship among AD, depression-related symptoms, and pro-inflammatory cytokines in the brain, and suggest that antidepressant-like impacts of minocycline could be due to its anti-inflammatory properties. This drug could be of potential interest for the treatment of depression in patients with Alzheimer's disease. 10.1007/s00213-018-5137-8

Sleep, major depressive disorder, and Alzheimer disease: A Mendelian randomization study. Neurology OBJECTIVE:To explore the causal relationships between sleep, major depressive disorder (MDD), and Alzheimer disease (AD). METHODS:We conducted bidirectional 2-sample Mendelian randomization analyses. Genetic associations were obtained from the largest genome-wide association studies currently available in UK Biobank (n = 446,118), Psychiatric Genomics Consortium (n = 18,759), and International Genomics of Alzheimer's Project (n = 63,926). We used the inverse variance-weighted Mendelian randomization method to estimate causal effects and weighted median and Mendelian randomization-Egger for sensitivity analyses to test for pleiotropic effects. RESULTS:We found that higher risk of AD was significantly associated with being a "morning person" (odds ratio [OR] 1.01, = 0.001), shorter sleep duration (self-reported: β = -0.006, = 1.9 × 10; accelerometer based: β = -0.015, = 6.9 × 10), less likely to report long sleep (β = -0.003, = 7.3 × 10), earlier timing of the least active 5 hours (β = -0.024, = 1.7 × 10), and a smaller number of sleep episodes (β = -0.025, = 5.7 × 10) after adjustment for multiple comparisons. We also found that higher risk of AD was associated with lower risk of insomnia (OR 0.99, = 7 × 10). However, we did not find evidence that these abnormal sleep patterns were causally related to AD or for a significant causal relationship between MDD and risk of AD. CONCLUSION:We found that AD may causally influence sleep patterns. However, we did not find evidence supporting a causal role of disturbed sleep patterns for AD or evidence for a causal relationship between MDD and AD. 10.1212/WNL.0000000000010463