Curcumin protects neuronal-like cells against acrolein by restoring Akt and redox signaling pathways.

International audienceThe aim of the present study was to examine the neuroprotective effect of curcumin against the toxicity induced by acrolein and to identify its cellular mechanisms and targets. Human neuroblastoma cells SK-N-SH were treated with acrolein. Curcumin, from 5 μM, was able to protect SK-N-SH cells against acrolein toxicity. The addition of curcumin restored the expression of γ-glutamylcysteine synthetase, reactive oxygen species, and reactive nitrogen species levels but had no effect on the decrease of glutathione (GSH) and on the elevation of protein carbonyls. Acrolein induced the activity of Nrf2, NF-κB, and Sirt1. These activations were prevented by the presence of curcumin. Acrolein also induced a decrease of the pAkt, which was counteracted by curcumin. To increase its solubility, we have encapsulated curcumin in a biodegradable poly(lactide-co-glycolide) based nanoparticulate formulation (Nps-Cur). Our results showed that 0.5 μM of Nps-Cur can protect neuronal cells challenged with acrolein while free curcumin was not able to display neuroprotection. Our results provided evidence that curcumin was able to protect SK-N-SH cells against acrolein toxicity. This protection is mediated through the antioxidant, the redox, and the survival regulated pathways by curcumin. Moreover, our results demonstrated that Nps-Cur had higher capacity than curcumin to protect SK-N-SH cells against acrolein

Blood-based redox-signature and their association to the cognitive scores in MCI and Alzheimer’s disease patients

International audienceOxidative stress plays a pivotal and early role in the pathophysiology of Alzheimer's disease (AD). There is convincing evidence that oxidative alterations in AD and in mild cognitive impairment (MCI) patients are not limited to the brain but are extended to the blood compartment. However, the oxidative pattern in plasma is still inconclusive. Moreover, their potential association with the clinical scores MMSE (Mini-Mental State Examination) and MoCA (Montreal Cognitive Assessment) is poorly investigated. The aim of our study was to establish a pattern of blood-based redox alterations in prodromal AD and their evolution during the progression of the disease. Our results showed a reduction in the total antioxidant capacity (TAC) and an increase of the stress-response proteins apolipoprotein J (ApoJ) and Klotho in MCI subjects. For the first time, we evidenced circulating-proteasome activity. We found that the alteration of the circulating-proteasome activity is associated with the accumulation of oxidized proteins in plasma form early AD. Interestingly, the TAC, the levels of vitamin D and the activity of proteasome were positively associated to the clinical scores MMSE and MoCA. The levels of protein carbonyls and of ApoJ were negatively associated to the MMSE and MoCA scores. The levels of apolipoprotein D (ApoD) were not different between groups. Interestingly, the receiver operating characteristic (ROC) curves analysis indicated that these redox markers provide a fair classification of different groups with high accuracy. Overall, our results strengthen the notion that some specific oxidative markers could be considered as non-invasive blood-based biomarkers for an early MCI diagnosis and AD progression

Cerebral Apolipoprotein D Exits the Brain and Accumulates in Peripheral Tissues

Apolipoprotein D (ApoD) is a secreted lipocalin associated with neuroprotection and lipid metabolism. In rodent, the bulk of its expression occurs in the central nervous system. Despite this, ApoD has profound effects in peripheral tissues, indicating that neural ApoD may reach peripheral organs. We endeavor to determine if cerebral ApoD can reach the circulation and accumulate in peripheral tissues. Three hours was necessary for over 40% of all the radiolabeled human ApoD (hApoD), injected bilaterally, to exit the central nervous system (CNS). Once in circulation, hApoD accumulates mostly in the kidneys/urine, liver, and muscles. Accumulation specificity of hApoD in these tissues was strongly correlated with the expression of lowly glycosylated basigin (BSG, CD147). hApoD was observed to pass through bEnd.3 blood brain barrier endothelial cells monolayers. However, cyclophilin A did not impact hApoD internalization rates in bEnd.3, indicating that ApoD exit from the brain is either independent of BSG or relies on additional cell types. Overall, our data showed that ApoD can quickly and efficiently exit the CNS and reach the liver and kidneys/urine, organs linked to the recycling and excretion of lipids and toxins. This indicated that cerebral overexpression during neurodegenerative episodes may serve to evacuate neurotoxic ApoD ligands from the CNS