Overview of alkyl quercetin lipophenol synthesis and its protective effect against carbonyl stress involved in neurodegeneration.

Oxidative stress and carbonyl stress resulting from the toxicity of small aldehydes are part of the detrimental mechanisms leading to neuronal cell loss involved in the progression of neurodegenerative diseases such as Alzheimer's disease. Polyunsaturated alkylated lipophenols represent a new class of hybrid molecules that combine the health benefits of anti-inflammatory omega-3 fatty acids with the anti-carbonyl and oxidative stress (anti-COS) properties of (poly)phenols in a single pharmacological entity. To investigate the therapeutic potential of quercetin-3-docosahexaenoic acid-7-isopropyl lipophenol in neurodegenerative diseases, three synthetic pathways using chemical or chemo-enzymatic strategies were developed to access milligram or gram scale quantities of this alkyl lipophenol. The protective effect of quercetin-3-DHA-7-iPr against cytotoxic concentrations of acrolein (a carbonyl stressor) was assessed in human SHSY-5Y neuroblastoma cells to underscore its ability to alleviate harmful mechanisms associated with carbonyl stress in the context of neurodegenerative diseases.

Microglial P2X4 receptors promote ApoE degradation and contribute to memory deficits in Alzheimer's disease.

Numerous evidences support that microglia contributes to the progression of Alzheimer's disease. P2X4 receptors are ATP-gated channels with high calcium permeability, which are de novo expressed in a subset of reactive microglia associated with various pathological contexts, contributing to microglial functions. P2X4 receptors are mainly localized in lysosomes and trafficking to the plasma membrane is tightly regulated. Here, we investigated the role of P2X4 in the context of Alzheimer's disease (AD). Using proteomics, we identified Apolipoprotein E (ApoE) as a specific P2X4 interacting protein. We found that P2X4 regulates lysosomal cathepsin B (CatB) activity promoting ApoE degradation; P2rX4 deletion results in higher amounts of intracellular and secreted ApoE in both bone-marrow-derived macrophage (BMDM) and microglia from APPswe/PSEN1dE9 brain. In both human AD brain and APP/PS1 mice, P2X4 and ApoE are almost exclusively expressed in plaque-associated microglia. In 12-month-old APP/PS1 mice, genetic deletion of P2rX4 reverses topographical and spatial memory impairment and reduces amount of soluble small aggregates of Aß1-42 peptide, while no obvious alteration of plaque-associated microglia characteristics is observed. Our results support that microglial P2X4 promotes lysosomal ApoE degradation, indirectly altering Aß peptide clearance, which in turn might promotes synaptic dysfunctions and cognitive deficits. Our findings uncover a specific interplay between purinergic signaling, microglial ApoE, soluble Aß (sAß) species and cognitive deficits associated with AD.

The pathomimetic oAß25-35 model of Alzheimer's disease: Potential for screening of new therapeutic agents.

Alzheimer's disease (AD) is the most common form of dementia in the elderly, currently affecting more than 40 million people worldwide. The two main histopathological hallmarks of AD were identified in the 1980s: senile plaques (composed of aggregated amyloid-ß (Aß) peptides) and neurofibrillary tangles (composed of hyperphosphorylated tau protein). In the human brain, both Aß and tau show aggregation into soluble and insoluble oligomers. Soluble oligomers of Aß include their most predominant forms - Aß1-40 and Aß1-42 - as well as shorter peptides such as Aß25-35 or Aß25-35/40. Most animal models of AD have been developed using transgenesis, based on identified human mutations. However, these familial forms of AD represent less than 1% of AD cases. In this context, the idea emerged in the 1990s to directly inject the Aß25-35 fragment into the rodent brain to develop an acute model of AD that could mimic the disease's sporadic forms (99% of all cases). This review aims to: (1) summarize the biological activity of Aß25-35, focusing on its impact on the main structural and functional alterations observed in AD (cognitive deficits, APP misprocessing, tau system dysfunction, neuroinflammation, oxidative stress, cholinergic and glutamatergic alterations, HPA axis dysregulation, synaptic deficits and cell death); and (2) confirm the interest of this pathomimetic model in AD research, as it has helped identify and characterize many molecules (marketed, in clinical development, and in preclinical testing), and to the development of alternative approaches for AD prevention and therapy. Today, the Aß25-35 model appears as a first-intent choice model to rapidly screen the symptomatic or neuroprotective potencies of new compounds, chemical series, or innovative therapeutic strategies.

Intranasal Administration of Nanovectorized Docosahexaenoic Acid (DHA) Improves Cognitive Function in Two Complementary Mouse Models of Alzheimer's Disease.

Polyunsaturated fatty acids (PUFAs) are a class of fatty acids that are closely associated with the development and function of the brain. The most abundant PUFA is docosahexaenoic acid (DHA, 22:6 n-3). In humans, low plasmatic concentrations of DHA have been associated with impaired cognitive function, low hippocampal volumes, and increased amyloid deposition in the brain. Several studies have reported reduced brain DHA concentrations in Alzheimer's disease (AD) patients' brains. Although a number of epidemiological studies suggest that dietary DHA consumption may protect the elderly from developing cognitive impairment or dementia including AD, several review articles report an inconclusive association between omega-3 PUFAs intake and cognitive decline. The source of these inconsistencies might be because DHA is highly oxidizable and its accessibility to the brain is limited by the blood-brain barrier. Thus, there is a pressing need for new strategies to improve DHA brain supply. In the present study, we show for the first time that the intranasal administration of nanovectorized DHA reduces Tau phosphorylation and restores cognitive functions in two complementary murine models of AD. These results pave the way for the development of a new approach to target the brain with DHA for the prevention or treatment of this devastating disease.

Seizure activity triggers tau hyperphosphorylation and amyloidogenic pathways.

OBJECTIVE: Although epilepsies and neurodegenerative disorders show pathophysiological similarities, their direct functional associations are unclear. Here, we tested the hypothesis that experimental seizures can induce tau hyperphosphorylation and amyloidogenic modifications over time, with intersections with neuroinflammation. METHODS: We used a model of mesial temporal lobe epilepsy (MTLE) where unilateral intrahippocampal injection of kainic acid (KA) in C57BL/6 mice elicits epileptogenesis and spontaneous focal seizures. We used a model of generalized status epilepticus (SE) obtained by intraperitoneal KA injection in C57BL/6 mice. We performed analyses and cross-comparisons according to a schedule of 72 h, 1 week, and 8 weeks after KA injection. RESULTS: In experimental MTLE, we show AT100, PHF1, and CP13 tau hyperphosphorylation during epileptogenesis (72 h-1 week) and long-term (8 weeks) during spontaneous seizures in the ipsilateral hippocampi, the epileptogenic zone. These pathological modifications extended to the contralateral hippocampus, a seizure propagating zone with no histological lesion or sclerosis. Two kinases, Cdk5 and GSK3ß, implicated in the pathological phosphorylation of tau, were activated. In this MTLE model, the induction of the amyloidogenic pathway (APP, C99, BACE1) was prominent and long-lasting in the epileptogenic zone. These Alzheimer's disease (AD)-relevant markers, established during seizure progression and recurrence, reciprocated an enduring glial (GFAP, Iba1) inflammation and the inadequate activation of the endogenous, anti-inflammatory, glucocorticoid receptor system. By contrast, a generalized SE episode provoked a predominantly transient induction of tau hyperphosphorylation and amyloidogenic markers in the hippocampus, along with resolving inflammation. Finally, we identified overlapping profiles of long-term hippocampal tau hyperphosphorylation by comparing MTLE to J20 mice, the latter a model relevant to AD. SIGNIFICANCE: MTLE and a generalized SE prompt persistent and varying tau hyperphosphorylation or amyloidogenic modifications in the hippocampus. In MTLE, an AD-relevant molecular trajectory intertwines with neuroinflammation, spatiotemporally involving epileptogenic and nonlesional seizure propagating zones.

New therapeutic horizons for plasma phospholipid transfer protein (PLTP): Targeting endotoxemia, infection and sepsis.

Phospholipid Transfer Protein (PLTP) transfers amphiphilic lipids between circulating lipoproteins and between lipoproteins, cells and tissues. Indeed, PLTP is a major determinant of the plasma levels, turnover and functionality of the main lipoprotein classes: very low-density lipoproteins (VLDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL). To date, most attention has been focused on the role of PLTP in the context of cardiometabolic diseases, with additional insights in neurodegenerative diseases and immunity. Importantly, beyond its influence on plasma triglyceride and cholesterol transport, PLTP plays a key role in the modulation of the immune response, with immediate relevance to a wide range of inflammatory diseases including bacterial infection and sepsis. Indeed, emerging evidence supports the role of PLTP, in the context of its association with lipoproteins, in the neutralization and clearance of bacterial lipopolysaccharides (LPS) or endotoxins. LPS are amphipathic molecules originating from Gram-negative bacteria which harbor major pathogen-associated patterns, triggering an innate immune response in the host. Although the early inflammatory reaction constitutes a key step in the anti-microbial defense of the organism, it can lead to a dysregulated inflammatory response and to hemodynamic disorders, organ failure and eventually death. Moreover, and in addition to endotoxemia and acute inflammation, small amounts of LPS in the circulation can induce chronic, low-grade inflammation with long-term consequences in several metabolic disorders such as atherosclerosis, obesity and diabetes. After an updated overview of the role of PLTP in lipid transfer, lipoprotein metabolism and related diseases, current knowledge of its impact on inflammation, infection and sepsis is critically appraised. Finally, the relevance of PLTP as a new player and novel therapeutic target in the fight against inflammatory diseases is considered.

Chronic Glucocorticoids Consumption Triggers and Worsens Experimental Alzheimer's Disease-Like Pathology by Detrimental Immune Modulations.

INTRODUCTION: Among the risk factors identified in the sporadic forms of Alzheimer's disease (AD), environmental and lifestyle elements are of growing interest. Clinical observations suggest that stressful events can anticipate AD onset, while stress-related disorders can promote AD. Here, we tested the hypothesis that a chronic treatment with glucocorticoids is sufficient to trigger or exacerbate AD molecular hallmarks. METHODS: We first validated a rat model of experimental chronic glucocorticoids (GC) consumption (corticosterone [CORT] in drinking water for 4 weeks). Then, to evaluate the consequences of chronic GC consumption on the onset of amyloid-ß (Aß) toxicity, animals chronically treated with GC were intracerebroventricularly injected with an oligomeric solution of Aß25-35 (oAß) (acute model of AD). We evaluated AD-related cognitive deficits and pathogenic mechanisms, with a special emphasis on neuroinflammatory markers. RESULTS: Chronic CORT consumption caused the inhibition of the nonamyloidogenic pathways, the impairment of Aß clearance processes and the induction of amyloidogenic pathways in the hippocampus. The principal enzymes involved in glucocorticoid receptor activation and Tau phosphorylation were upregulated. Importantly, the AD-like phenotype triggered by chronic CORT was analogous to the one caused by oAß. These molecular commonalities across models were independent from inflammation, as chronic CORT was immunosuppressive while oAß was pro-inflammatory. When chronic CORT consumption anticipated the induction of the oAß pathology, we found a potentiation of neuroinflammatory processes associated with an exacerbation of synaptic and memory deficits but also an aggravation of AD-related hallmarks. DISCUSSION/CONCLUSION: This study unravels new functional outcomes identifying chronic CORT consumption as a main risk factor for AD and suggests that glucocorticoid-based therapies should be prescribed with caution in populations with AD risk.

Investigation of the spontaneous nanoemulsification process with medium- and long-chain triglycerides.

Oil-in-water nanoemulsions are used in numerous biomedical applications as delivery systems. The droplet size in the nanometer range and their composition were extensively developed for carrying and enhancing the absorption of lipophilic drugs and lipids of interest. In the present study, critical parameters involved in the spontaneous nanoemulsification process such as the temperature, the oil type, the surfactant-to-oil and water-to-oil ratios were investigated. The aim was to design a solvent-free procedure for the spontaneous nanoemulsification at a low temperature of a large variety of triglycerides including vegetable oils. Nanoemulsification of medium-chain triglyceride (MCT) was not dependent on the temperature while nanodroplets of long-chain triglycerides (LCT) were only obtained by reaching the cloud point of ethoxylated surfactant Kolliphor® HS15. The molar volume of triglycerides was considered as a predictive parameter governing both, the spontaneous nanoemulsification at low temperature and the Ostwald ripening rate. The physical mixture of MCT and LCT was a promising strategy to prepare stable and fine nanoemulsions at 37 °C. They were characterized by a hydrodynamic diameter comprised between 20 and 30 nm and a narrow size distribution. These findings pave the way to new applications for the parenteral nutrition and the delivery of thermosensitive drugs and lipophilic molecules such as antioxidants.

Glucocorticoid receptors signaling impairment potentiates amyloid-ß oligomers-induced pathology in an acute model of Alzheimer's disease.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis occurs early in Alzheimer's disease (AD), associated with elevated circulating glucocorticoids (GC) and glucocorticoid receptors (GR) signaling impairment. However, the precise role of GR in the pathophysiology of AD remains unclear. Using an acute model of AD induced by the intracerebroventricular injection of amyloid-ß oligomers (oAß), we analyzed cellular and behavioral hallmarks of AD, GR signaling pathways, processing of amyloid precursor protein, and enzymes involved in Tau phosphorylation. We focused on the prefrontal cortex (PFC), particularly rich in GR, early altered in AD and involved in HPA axis control and cognitive functions. We found that oAß impaired cognitive and emotional behaviors, increased plasma GC levels, synaptic deficits, apoptosis and neuroinflammatory processes. Moreover, oAß potentiated the amyloidogenic pathway and enzymes involved both in Tau hyperphosphorylation and GR activation. Treatment with a selective GR modulator (sGRm) normalized plasma GC levels and all behavioral and biochemical parameters analyzed. GR seems to occupy a central position in the pathophysiology of AD. Deregulation of the HPA axis and a feed-forward effect on PFC GR sensitivity could participate in the etiology of AD, in perturbing Aß and Tau homeostasis. These results also reinforce the therapeutic potential of sGRm in AD.

Fungicide Residues Exposure and ß-amyloid Aggregation in a Mouse Model of Alzheimer's Disease.

BACKGROUND: Pesticide residues have contaminated our environment and nutrition over the last century. Although these compounds are present at very low concentrations, their long-term effects on human health is of concern. The link between pesticide residues and Alzheimer's disease is not clear and difficult to establish. To date, no in vivo experiments have yet modeled the impact of this chronic contamination on neurodegenerative disorders. OBJECTIVES: We investigated the impact of fungicide residues on the pathological markers of Alzheimer's disease in a transgenic mouse model. METHODS: Transgenic (J20, hAPPSw/Ind) mice were chronically exposed to a cocktail of residues of cyprodinil, mepanipyrim, and pyrimethanil at 0.1µg/L in their drinking water for 9 months. We assessed the effects of fungicide residues on the pathological markers of the disease including Aß aggregates, neuroinflammation, and neuronal loss. Then, we studied the dynamics of Aß aggregation in vivo via a longitudinal study using two-photon microscopy. Finally, we investigated the molecular mechanisms involved in the production and clearance of Aß peptides. RESULTS: We found that a chronic exposure to three fungicide residues exacerbated aggregation, microgliosis, and neuronal loss. These fungicides also increased vascular amyloid aggregates reminiscent of cerebral amyloid angiopathy between 6 and 9 months of treatment. The mechanism of action revealed that fungicides promoted Aß peptide fibril formation in vitro and involved an in vivo overexpression of the levels of the ß-secretase-cleaving enzyme (BACE1) combined with impairment of Aß clearance through neprylisin (NEP). CONCLUSIONS: Chronic exposure of the J20 mouse model of Alzheimer's disease to a cocktail of fungicides, at the regulatory concentration allowed in tap water (0.1µg/L), strengthened the preexisting pathological markers: neuroinflammation, Aß aggregation, and APP ß-processing. We hypothesize prevention strategies toward pesticide long-term exposure may be an alternative to counterbalance the lack of treatment and to slow down the worldwide Alzheimer's epidemic. https://doi.org/10.1289/EHP5550.

Is AD a Stress-Related Disorder? Focus on the HPA Axis and Its Promising Therapeutic Targets.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has important health and economic impacts in the elderly. Despite a better understanding of the molecular mechanisms leading to the appearance of major pathological hallmarks (senile plaques and neurofibrillary tangles), effective treatments are still lacking. Sporadic AD forms (98% of all cases) are multifactorial, and a panoply of risk factors have been identified. While the major risk factor is aging, growing evidence suggests that chronic stress or stress-related disorders increase the probability to develop AD. An early dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis or stress axis) has been observed in patients. The direct consequence of such perturbation is an oversecretion of glucocorticoids (GC) associated with an impairment of its receptors (glucocorticoid receptors, GR). These steroids hormones easily penetrate the brain and act in synergy with excitatory amino acids. An overexposure could be highly toxic in limbic structures (prefrontal cortex and hippocampus) and contribute in the cognitive decline occurring in AD. GC and GR dysregulations seem to be involved in lots of functions disturbed in AD and a vicious cycle appears, where AD induces HPA axis dysregulation, which in turn potentiates the pathology. This review article presents some preclinical and clinical studies focusing on the HPA axis hormones and their receptors to fight AD. Due to its primordial role in the maintenance of homeostasis, the HPA axis appears as a key-actor in the etiology of AD and a prime target to tackle AD by offering multiple angles of action.

Central Role of Glucocorticoid Receptors in Alzheimer's Disease and Depression.

Alzheimer's disease (AD) is the principal neurodegenerative pathology in the world displaying negative impacts on both the health and social ability of patients and inducing considerable economic costs. In the case of sporadic forms of AD (more than 95% of patients), even if mechanisms are unknown, some risk factors were identified. The principal risk is aging, but there is growing evidence that lifetime events like chronic stress or stress-related disorders may increase the probability to develop AD. This mini-review reinforces the rationale to consider major depressive disorder (MDD) as an important risk factor to develop AD and points the central role played by the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoids (GC) and their receptors (GR) in the etiology of MDD and AD. Several strategies directly targeting GR were tested to neutralize the HPA axis dysregulation and GC overproduction. Given the ubiquitous expression of GR, antagonists have many undesired side effects, limiting their therapeutic potential. However, a new class of molecules was developed, highly selective and acting as modulators. They present the advantage to selectively abrogate pathogenic GR-dependent processes, while retaining beneficial aspects of GR signaling. In fact, these "selective GR modulators" induce a receptor conformation that allows activation of only a subset of downstream signaling pathways, explaining their capacity to combine agonistic and antagonistic properties. Thus, targeting GR with selective modulators, alone or in association with current strategies, becomes particularly attractive and relevant to develop novel preventive and/or therapeutic strategies to tackle disorders associated with a dysregulation of the HPA axis.

Association of circulating metabolites with healthy diet and risk of cardiovascular disease: analysis of two cohort studies.

Diet may modify metabolomic profiles towards higher or lower cardiovascular disease (CVD) risk. We aimed to identify metabolite profiles associated with high adherence to dietary recommendations - the Alternative Healthy Eating Index (AHEI) - and the extent to which metabolites associated with AHEI also predict incident CVD. Relations between AHEI score and 80 circulating lipids and metabolites, quantified by nuclear magnetic resonance metabolomics, were examined using linear regression models in the Whitehall II study (n = 4824, 55.9 ± 6.1 years, 28.0% women) and were replicated in the Cardiovascular Risk in Young Finns Study (n = 1716, 37.7 ± 5.0 years, 56.3% women). We used Cox models to study associations between metabolites and incident CVD over the 15.8-year follow-up in the Whitehall II study. After adjustment for confounders, higher AHEI score (indicating healthier diet) was associated with higher degree of unsaturation of fatty acids (FA) and higher ratios of polyunsaturated FA, omega-3 and docosahexaenoic acid relative to total FA in both Whitehall II and Young Finns studies. A concordance of associations of metabolites with higher AHEI score and lower CVD risk was observed in Whitehall II. Adherence to healthy diet seems to be associated with specific FA that reduce risk of CVD.

Low doses of bioherbicide favour prion aggregation and propagation in vivo.

Public concerns over the use of synthetic pesticides are growing since many studies have shown their impact on human health. A new environmental movement in occidental countries promoting an organic agriculture favours the rebirth of botanical pesticides. These products confer an effective alternative to chemical pesticides such as glyphosate. Among the biopesticides, the α-terthienyls found in the roots of Tagetes species, are powerful broad-spectrum pesticides. We found that an α-terthienyl analogue with herbicidal properties, called A6, triggers resistant SDS oligomers of the pathogenic prion protein PrPSc (rSDS-PrPSc) in cells. Our main question is to determine if we can induce those rSDS-PrPSc oligomers in vitro and in vivo, and their impact on prion aggregation and propagation. Using wild-type mice challenged with prions, we showed that A6 accelerates or slows down prion disease depending on the concentration used. At 5 mg/kg, A6 is worsening the pathology with a faster accumulation of PrPSc, reminiscent to soluble toxic rSDS-PrPSc oligomers. In contrast, at 10 and 20 mg/kg of A6, prion disease occurred later, with less PrPSc deposits and with rSDS-PrPSc oligomers in the brain reminiscent to non-toxic aggregates. Our results are bringing new openings regarding the impact of biopesticides in prion and prion-like diseases.

Deletion of plasma Phospholipid Transfer Protein (PLTP) increases microglial phagocytosis and reduces cerebral amyloid-ß deposition in the J20 mouse model of Alzheimer's disease.

Plasma phospholipid transfer protein (PLTP) binds and transfers a number of amphipathic compounds, including phospholipids, cholesterol, diacylglycerides, tocopherols and lipopolysaccharides. PLTP functions are relevant for many pathophysiological alterations involved in neurodegenerative disorders (especially lipid metabolism, redox status, and immune reactions), and a significant increase in brain PLTP levels was observed in patients with Alzheimer's disease (AD) compared to controls. To date, it has not been reported whether PLTP can modulate the formation of amyloid plaques, i.e. one of the major histopathological hallmarks of AD. We thus assessed the role of PLTP in the AD context by breeding PLTP-deficient mice with an established model of AD, the J20 mice. A phenotypic characterization of the amyloid pathology was conducted in J20 mice expressing or not PLTP. We showed that PLTP deletion is associated with a significant reduction of cerebral Aß deposits and astrogliosis, which can be explained at least in part by a rise of Aß clearance through an increase in the microglial phagocytic activity and the expression of the Aß-degrading enzyme neprilysin. PLTP arises as a negative determinant of plaque clearance and over the lifespan, elevated PLTP activity could lead to a higher Aß load in the brain.

PhosphoLipid transfer protein (PLTP) exerts a direct pro-inflammatory effect on rheumatoid arthritis (RA) fibroblasts-like-synoviocytes (FLS) independently of its lipid transfer activity.

Rheumatoid arthritis (RA) is a chronic inflammatory rheumatic disease with modification of lipids profile and an increased risk of cardiovascular events related to inflammation. Plasma phospholipid transfer protein (PLTP) exerts a lipid transfer activity through its active form. PLTP can also bind to receptors such as ATP-binding cassette transporter A1 (ABCA1). In addition to its role in lipoprotein metabolism and atherosclerosis, the latest advances came in support of a complex role of PLTP in the regulation of the inflammatory response, both with pro-inflammatory or anti-inflammatory properties. The aim of the present study was to decipher the role of PLTP in joint inflammation and to assess its relevance in the context of RA. PLTP expression was examined by western-blot and by immunochemistry. ABCA1 expression was analyzed by flow cytometry. Lipid transfer activity of PLTP and pro-inflammatory cytokines were measured in sera and synovial fluid (SF) from RA patients and controls (healthy subjects or osteoarthritis patients [OA]). FLS were treated with both lipid-transfer active form and inactive form of recombinant human PLTP. IL-8, IL-6, VEGF and MMP3 produced by FLS were assessed by ELISA, and proliferation by measuring 3H-Thymidine incorporation. RA synovial tissues showed higher PLTP staining than OA and PLTP protein levels were also significantly higher in RA-FLS. In addition, RA, unlike OA patients, displayed elevated levels of PLTP activity in SF, which correlated with pro-inflammatory cytokines. Both lipid-transfer active and inactive forms of PLTP significantly increased the production of cytokines and proliferation of FLS. ABCA1 was expressed on RAFLS and PLTP activated STAT3 pathway. To conclude, PLTP is highly expressed in the joints of RA patients and may directly trigger inflammation and FLS proliferation, independently of its lipid transfer activity. These results suggest a pro-inflammatory role for PLTP in RA.

Brain Vitamin E Deficiency During Development Is Associated With Increased Glutamate Levels and Anxiety in Adult Mice.

Vitamin E, the most important lipophilic radical scavenging antioxidant in vivo, has a pivotal role in brain. In an earlier study, we observed that adult mice with a defect in the gene encoding plasma phospholipid transfer protein (PLTP) display a moderate reduction in cerebral vitamin E levels, and exacerbated anxiety despite normal locomotion and memory functions. Here we sought to determine whether dietary vitamin E supplementation can modulate neurotransmitter levels and alleviate the increased anxiety phenotype of PLTP-deficient (PLTP -/-) mice. To address this question, a vitamin E-enriched diet was used, and two complementary approches were implemented: (i) "early supplementation": neurotransmitter levels and anxiety were assessed in 6 months old PLTP -/- mice born from vitamin E-supplemented parents; and (ii) "late supplementation": neurotransmitter levels and anxiety were assessed in 6 months old PLTP -/- mice fed a vitamin E-enriched diet from weaning. Our results show for the first time that an inadequate supply of vitamin E during development, due to moderate maternal vitamin E deficiency, is associated with reduced brain vitamin E levels at birth and irreversible alterations in brain glutamate levels. They also suggest this deficiency is associated with increased anxiety at adulthood. Thus, the present study leads to conclude on the importance of the micronutrient vitamin E during pregnancy.

Plasma cholesterol level determines in vivo prion propagation.

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases with an urgent need for therapeutic and prophylactic strategies. At the time when the blood-mediated transmission of prions was demonstrated, in vitro studies indicated a high binding affinity of the scrapie prion protein (PrPSc) with apoB-containing lipoproteins, i.e., the main carriers of cholesterol in human blood. The aim of the present study was to explore the relationship between circulating cholesterol-containing lipoproteins and the pathogenicity of prions in vivo. We showed that, in mice with a genetically engineered deficiency for the plasma lipid transporter, phospholipid transfer protein (PLTP), abnormally low circulating cholesterol concentrations were associated with a significant prolongation of survival time after intraperitoneal inoculation of the 22L prion strain. Moreover, when circulating cholesterol levels rose after feeding PLTP-deficient mice a lipid-enriched diet, a significant reduction in survival time of mice together with a marked increase in the accumulation rate of PrPSc deposits in their brain were observed. Our results suggest that the circulating cholesterol level is a determinant of prion propagation in vivo and that cholesterol-lowering strategies might be a successful therapeutic approach for patients suffering from prion diseases.

Recombinant human plasma phospholipid transfer protein (PLTP) to prevent bacterial growth and to treat sepsis.

Although plasma phospholipid transfer protein (PLTP) has been mainly studied in the context of atherosclerosis, it shares homology with proteins involved in innate immunity. Here, we produced active recombinant human PLTP (rhPLTP) in the milk of new lines of transgenic rabbits. We successfully used rhPLTP as an exogenous therapeutic protein to treat endotoxemia and sepsis. In mouse models with injections of purified lipopolysaccharides or with polymicrobial infection, we demonstrated that rhPLTP prevented bacterial growth and detoxified LPS. In further support of the antimicrobial effect of PLTP, PLTP-knocked out mice were found to be less able than wild-type mice to fight against sepsis. To our knowledge, the production of rhPLTP to counter infection and to reduce endotoxemia and its harmful consequences is reported here for the first time. This paves the way for a novel strategy to satisfy long-felt, but unmet needs to prevent and treat sepsis.