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Abstract: Alzheimer''s disease (AD) is a multifactorial disorder characterized by the presence of amyloid plaques and neurofibrillary tangles (NFTs). Rare early-onset forms of AD are associated with autosomal dominant mutations in the amyloid precursor protein gene, presenilin 1 gene, or presenilin 2 gene. The late-onset form of the disease (LOAD) is the most common form. The causes of LOAD are not yet clarified, but several environmental and genetic risk factors have been identified. Numerous studies have highlighted a role for free radical-mediated injury to brain regions of this illness. In addition, studies from mild cognitive impairment patients suggest that oxidative stress is an early event in the pathogenesis of AD. The associations between these markers of free radical damage and the pathogenic cascades involved in AD are complex. Over the past 2 decades, a number of mouse models have been created to recapitulate the major neuropathological hallmarks of AD, namely amyloid plaques and NFTs. These mice recapitulate many, although not all, of the key features of AD. Some strains of transgenic mice develop amyloid plaques, some accumulate NFTs, and some do both. Here we review the evidence for increased free radical-mediated damage to the brain with particular attention to the stage of the disease in various transgenic models of AD related to the amyloid-β cascade. [Copyright &y& Elsevier]

Abstract: Aging is the major risk factor for neurodegenerative diseases such as Alzheimer''s and Parkinson''s diseases. A large body of evidence indicates that oxidative stress is involved in the pathophysiology of these diseases. Oxidative stress can induce neuronal damages, modulate intracellular signaling, ultimately leading to neuronal death by apoptosis or necrosis. Thus antioxidants have been studied for their effectiveness in reducing these deleterious effects and neuronal death in many in vitro and in vivo studies. Increasing number of studies demonstrated the efficacy of polyphenolic antioxidants from fruits and vegetables to reduce or to block neuronal death occurring in the pathophysiology of these disorders. These studies revealed that other mechanisms than the antioxidant activities could be involved in the neuroprotective effect of these phenolic compounds. We will review some of these mechanisms and particular emphasis will be given to polyphenolic compounds from green tea, the Ginkgo biloba extract EGb 761, blueberries extracts, wine components and curcumin. [Copyright &y& Elsevier]

Nanoparticulate carriers, often referred to as nanoparticles (NPs), represent an important pharmacological advance for drug protection and tissue-specific drug delivery. Accessing the central nervous system (CNS), however, is a complex process regulated by mainly three brain barriers. While some leukocyte (i.e., immune cell) subsets are equipped with the adequate molecular machinery to infiltrate the CNS in physiological and/or pathological contexts, the successful delivery of NPs into the CNS remains hindered by the tightness of the brain barriers. Here, we present an overview of the three major brain barriers and the mechanisms allowing leukocytes to migrate across each of them. We subsequently review different immune-inspired and -mediated strategies to deliver NPs into the CNS. Finally, we discuss the prospect of exploiting leukocyte trafficking mechanisms for further progress. Most drug delivery strategies perform suboptimally in the CNS due to the presence of three major brain barriers: the blood–brain barrier, the blood–leptomeningeal barrier, and the blood–cerebrospinal fluid barrier. Immune cells use a plethora of molecules to bypass the different barriers and infiltrate the CNS under homeostasis and in diverse pathological contexts. Nanoparticulate carriers, often shortened to nanoparticles (NPs), have recently emerged as superior vehicles capable of protecting drugs while also promoting tissue-specific delivery, but remain ineffective in transporting pharmaceutical agents into the CNS. Exploiting the molecular and cellular pathways used by immune cells to overcome the protective brain barriers may prove useful for enhancing NP delivery into the CNS. [ABSTRACT FROM AUTHOR]

Abstract: Parkinson’s disease (PD) is one of the most common age related neurodegenerative disease and affects millions of people worldwide. Strong evidence suggests a role for oxidative stress and mitochondrial dysfunctions in the pathogenesis of PD. Recent epidemiologic and toxicological studies have shown that environmental factors, especially herbicides such as paraquat and diquat represent one of the primary classes of neurotoxic agents associated with PD. The objective of our study was to investigate the neuroprotective effects of the standardized extract of Bacopa monniera (BM) against paraquat/diquat-induced toxicity and to elucidate the mechanisms underlying this protection. Our results showed that a pre-treatment with the BM extract, from 20.0μg/ml, protected the rat dopaminergic PC12 cell line against paraquat/diquat-induced toxicity in various cell survival assays. We demonstrated that BM pre-treatment, from 5.0μg/ml, could prevent the generation of intracellular reactive oxygen species (ROS), decreased mitochondrial superoxide levels and depolarized the mitochondria. BM pre-treatment also increased tyrosine hydroxylase (TH) levels and antioxidant defense systems such as γ-glutamylcysteine synthetase (γ-GCS) and thioredoxin1 (Trx1) levels. Furthermore, BM pre-treatment prevented the activation of Akt and heat shock protein90 (HSP90) proteins. Thus, our findings demonstrated that BM can protect PC12 cells through modulating cellular redox pathways which are altered in PD and could have a therapeutic application in the prevention of PD. [Copyright &y& Elsevier]

Abstract: The role of nuclear factor kappa B (NF-κB) in oxidative stress, and most recently in pro- and anti-apoptotic-related mechanistic pathways, has well been established. Because of the dual nature of NF-κB, the wide range of genes it regulates and the plethora of stimuli that activate it, various studies addressing the functional role of NF-κB proteins have resulted in a number of differing findings. The present study examined the effect of a stimulus-free environment on the frontal cortex of mice brain with the p50 subunit of NF-κB knocked out p50 (−/−). Homozygous p50 mice knockout (KO) and wild type (WT) were used, and at 7–9 weeks they were sacrificed and various brain regions dissected. We analyzed the levels of oxidation in the frontal cortex of both the p50 (−/−) and WT mice. There was a significant reduction in the levels of protein-bound 4-hydroxynonenal (HNE) [a lipid peroxidation product], 3-nitrotyrosine (3NT), and protein carbonyls in the p50 (−/−) mice when compared to the WT. A proteomic profile analysis identified ATP synthase gamma chain, ubiquinol-cyt-C reductase, heat shock protein 10 (Hsp10), fructose bisphosphate aldolase C, and NADH–ubiquinone oxidoreductase as proteins whose expressions were significantly increased in the p50 (−/−) mice compared to the WT. With the reduction in the levels of oxidative stress and the increase in expression of key proteins in the p50 (−/−) brain, this study suggests that the p50 subunit can potentially be targeted for the development of therapeutic interventions in disorders in which oxidative stress plays a key role. [Copyright &y& Elsevier]

Accumulating evidence suggests that the propagation of hyperphosphorylation of tau protein and the amyloid-β peptide can be mediated by extracellular vesicles (EVs) and be associated with the onset and the progression of Alzheimer's disease (AD). As EVs may transfer between the brain and the blood, we have thus hypothesized that the total plasma EVs (pEVs) may contain potential markers to predict the mild cognitive impairment (MCI) and AD progression. We have thus quantified AD-related proteins in isolated pEVs from controls, MCI and AD subjects. In pEVs, we observed early changes of total tau (tTau), amyloid precursor protein levels, and phospho-tau (pTau)-T181/tTau ratio from MCI subjects and late increases of Aβ42 and pTau-T181 levels from patients with moderate AD. Interestingly, abnormal amyloid precursor protein levels and pTau-T181/tTau ratio in pEVs demonstrated a high accuracy to define MCI and AD staging. Although larger samples sizes will be needed to generate well-powered investigations, these preliminary results highlighted the potential of AD-related proteins enriched in pEVs as a sensitive tool for differentiating patients with MCI to patients with AD and monitoring AD progression. • Circulating EVs contained potential biomarkers for AD. • Aβ42 and pTau-T181 levels in circulating EVs represent late biomarkers in AD. • Modifications of tTau and APP levels, the pTau-T181/tTau ratio in circulating EVs correspond to early events in MCI and AD. • Systemic variations of APP in EVs could indicate an early impairment in regulating endocytosis and trafficking. [ABSTRACT FROM AUTHOR]

Abstract Oxidative 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. Graphical abstract fx1 Highlights • Early Impairment of the plasma ability to degrade H2O2 in MCI patients. • Rise of some stress‐response proteins from the MCI status. • Inverse correlation between the circulating‐proteasome activity and protein oxidation in AD plasma. • Some plasma oxidative markers are linked to cognitive scores (MoCA and MMSE). • A combination of oxidative markers can be considered for the MCI diagnosis and the progression of AD. [ABSTRACT FROM AUTHOR]

Highlights: [•] Homocysteic acid (HCA) induces neurotoxicity in dose- and time-dependent manners. [•] HCA decreases the ratio of Bcl-2/Bax, but in a Caspase-3-independent way. [•] HCA induces oxidative stress and decreased the levels of the Nrf2 and HO-1. [•] The toxicity of HCA is attenuated by SP600125. [•] HCA increases the levels of p-c-Jun and p-JNK. [Copyright &y& Elsevier]

Abstract: The pathologic mechanisms of Alzheimer''s disease (AD) have not been fully uncovered. Acrolein, a ubiquitous dietary pollutant and by-product of oxidative stress, can induce cytotoxicity in neurons, which might play an important role in the etiology of AD. Here, we examined the effects of Acrolein on the AD pathologies in vitro and in vivo. We found Acrolein induced HT22 cells death in concentration- and time-dependent manners. Interestingly, Acrolein increased proteins’ levels of amyloid precursor protein (APP), β-secretase (BACE-1) and the amyloid β-peptide transporter receptor for advanced glycation end products, and decreased A-disintegrin and metalloprotease (ADAM) 10 levels. In vivo, chronic oral exposure to Acrolein (2.5mg/kg/day by intragastric gavage for 8 weeks) induced mild cognitive declination and pyknosis/atrophy of hippocampal neurons. The activity of superoxide dismutase was down-regulated while the level of malondialdehyde was up-regulated in rat brain. Moreover, Acrolein resulted in activation of astrocytes, up-regulation of BACE-1 in cortex and down-regulation of ADAM-10 in hippocampus and cortex. Taken together, our findings suggest that exposure to Acrolein induces AD-like pathology in vitro and in vivo. Scavenging Acrolein might be beneficial for the therapy of AD. [Copyright &y& Elsevier]

Abstract: Acrolein-induced oxidative stress is hypothesized to involve in the etiology of Alzheimer''s disease (AD). Caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) have antioxidative and neuroprotective properties. The present study investigated the protective effects of CA/CAPE on acrolein-induced oxidative neuronal toxicity. HT22 mouse hippocampal cells were pretreated with CA/CAPE and then exposed to acrolein. Cell viability, intracellular reactive oxygen species (ROS), and glutathione (GSH) level were measured. MAPKs and Akt/GSK3β signaling proteins as well as α/β-secretase of amyloid protein precursor were assayed by Western blotting. Pretreatment with CA/CAPE significantly attenuated acrolein-induced neurotoxicity, ROS accumulation, and GSH depletion. Further study suggested that CA/CAPE showed protective effects against acrolein by modulating MAPKs and Akt/GSK3β signaling pathways. Moreover, CA/CAPE restored the changes of β-secretase (BACE-1) and/or activation of α-secretase (ADAM-10) induced by acrolein. These findings suggest that CA/CAPE may provide a promising approach for the treatment of acrolein-related neurodegenerative diseases, such as AD. [Copyright &y& Elsevier]

Abstract: The aims of this work were 1) to determine the bioactivities resulting from the hydrolysis of soy (Glycine max) proteins isolate (SPI) by a double enzymatic treatment of pepsin and pancreatin and 2) to investigate whether fractionation of the protein hydrolysates by two ultrafiltration techniques using either hollow fiber (HF) or spiral-wounded (SW) membrane (10kDa cut-off), increases biological activity of the recovered peptides. The focus was on the screening of bioactivity of the peptide fractions using multiple in vitro bioassays such as the proliferation of cancer cells, destruction of murine norovirus-1 (MNV-1), anti-oxidative and immuno-modulating properties, and finally glucose metabolism in a muscle cell line. Significant biological effects of the peptides for both antioxidant capacity (ORAC assay) and metabolism (muscle glucose uptake assay) were found. These results show that ultrafiltration of SPI hydrolysates is a convenient process for the recovery of large amount of bioactive peptides. [Copyright &y& Elsevier]

Abstract: Aβ peptide-induced toxicity is mediated through oxidative stress and is associated with an activation of intracellular signaling such as the redox-sensitive transcription factor NF-κB and MAPK pathways. We demonstrate on neuroblastoma cell line N2a that EGb 761 could prevent the activation of NF-κB, ERK1/2, and JNK pathways induced by Aβ. Furthermore, our results show that EGb 761 can also activate SIRT1. This activation could explain the reduction of NF-kB activity by promoting the deacetylation of Lys310 of subunit p65. On the other hand, aggregation of Aβ to insoluble fibrils is a crucial step in Aβ-induced neurotoxicity. Using fluorescence spectroscopy with thioflavin T and electron microscopy, we demonstrate that EGb 761 and its flavonoid fraction (CP 205) could prevent the Aβ fibril (fAβ) formation in vitro. Finally we show that Aβ is less toxic to N2a neuroblastoma cells when the peptide is previously incubated with the flavonoid fraction or EGb 761 during the fibril formation period. On the other hand, the ginkgolide compound BN 52021 was not able to prevent fAβ formation. Interestingly it could also protect cells against Aβ toxicity. Our study demonstrates that the protection of neuronal cells by EGb 761 against Aβ could involve different mechanisms as the regulation of several key intracellular pathways and the inhibition of fAβ formation and implicate more than its free radical scavenging property. [Copyright &y& Elsevier]

Zwitterion polymers with strong antifouling properties have been suggested as the prime alternative to polyethylene glycol (PEG) for drug nanocarriers surface coating. It is believed that PEG coating shortcomings, such as immune responses and incomplete protein repellency, could be overcome by zwitterionic polymers. However, no systematic study has been conducted so far to complete a comparative appraisal of PEG and zwitterionic-coating effects on nanoparticles (NPs) stealthness, cell uptake, cell barrier translocation and biodistribution in the context of nanocarriers brain targeting. Core-shell polymeric particles with identical cores and a shell of either PEG or poly(2-methacryloyloxyethyl phosphorylcholine (PMPC) were prepared by impinging jet mixer nanoprecipitation. NPs with similar size and surface potential were systematically compared using in vitro and in vivo assays. NPs behavior differences were rationalized based on their protein-particles interactions. PMPC-coated NPs were significantly more endocytosed by mouse macrophages or brain resident macrophages compared to PEGylated NPs but exhibited the remarkable ability to cross the blood-brain barrier in in vitro models. Nanoscale flow cytometry assays showed significantly more adsorbed proteins on PMPC-coated NPs than PEG-coated NPs. In vivo , distribution in zebrafish larvae, showed a strong propensity for PMPC-coated NPs to adhere to the vascular endothelium, while PEG-coated NPs were able to circulate for a longer time and escape the bloodstream to penetrate deep into the cerebral tissue. The stark differences between these two types of particles, besides their similarities in size and surface potential, points towards the paramount role of surface chemistry in controlling NPs fate likely via the formation of distinct protein corona for each coating. [Display omitted] [ABSTRACT FROM AUTHOR]

An early diagnosis of Alzheimer's disease (AD) is required for early and more effective treatment. Oxidative stress plays an early role in AD and could promote the formation of advanced glycation end products (AGEs) in AD brains. However, the peripheral association of specific AGEs and oxidative markers with cognitive decline remains to be defined in order to establish a clinical signature for an early diagnosis. Objectives: To measure the total antioxidant capacity (TAC), the levels of protein carbonyl (PC), AGEs precursors (methylglyoxal, MG; glyoxal, GO) and some specific AGEs (pentosidine; carboxylmethyl lysine, CML) and their association with clinical scores (MMSE and MoCA). Methods: These markers were measured in blood from patients with MCI (mild cognitive impairment) and AD at different stages and from age-matched controls by Western blot, ELISA or HPLC. Results: A decrease of TAC and an increase of AGEs precursor's levels (MG and GO) are observed in MCI patients. PC and CML levels raised later in AD groups. Pentosidine levels were not different. Interestingly, PC and CML levels are correlated with cognitive scores. Conclusion: Our results demonstrate that TAC decreases early in MCI stage while some oxidative markers and AGEs precursors increase and are correlated with cognitive decline. Overall, some oxidative stress markers have a potential as biomarkers for AD. [ABSTRACT FROM AUTHOR]