Julien BENSALEM - Academia.edu (original) (raw)

Papers by Julien BENSALEM

Nature Medicine

Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in publishe... more Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

HAL (Le Centre pour la Communication Scientifique Directe), Mar 14, 2014

Biochemical and Biophysical Research Communications

Degradation and clearance of cellular waste in the autophagic and endo-lysosomal systems is impor... more Degradation and clearance of cellular waste in the autophagic and endo-lysosomal systems is important for normal physiology and prevention of common late-onset diseases such as Alzheimer's disease (AD). Phosphatidylinostol-binding clathrin assembly protein (PICALM) is a robust AD risk factor gene and encodes an endosomal protein clathrin-binding cytosolic protein, reduction of which is known to exacerbate tauopathy. Although PICALM is known to regulate initiation of autophagy, its role in maturation of lysosomal enzymes required for proteolysis has not been studied. We sought to determine the importance of PICALM for cellular degradative function by disrupting exon 1 of PICALM using CRISPR/Cas9 in HeLa cells. PICALM disruption increased numbers of early endosomes. Proteomic analysis of endosome-enriched samples showed that disrupting exon 1 of PICALM increased the abundance of lysosomal enzymes in these organelles, and western blotting revealed disruption to processing and maturation of the lysosomal protease, cathepsin D, and a deficit in autophagy. This study shows PICALM is important for the correct maturation of lysosomal enzymes and efficient proteolytic function in the lysosome.

HAL (Le Centre pour la Communication Scientifique Directe), Dec 10, 2013

HAL (Le Centre pour la Communication Scientifique Directe), Apr 9, 2014

Background Autophagy is a cellular process that cleanses cells and is particularly important duri... more Background Autophagy is a cellular process that cleanses cells and is particularly important during ageing. Autophagy has been extensively studied in vitro and in animal models and is known to be sensitive to nutrition. However, human data are limited because autophagic flux (autophagic degradative activity) has been challenging to measure in humans. This protocol paper describes the Break-Fast study, in which autophagic flux will be measured using a recently developed blood test, before and after ingestion of whey protein. This aims to determine whether an acute nutritional intervention can change autophagy in humans. Methods A minimum of forty healthy participants (both male and female) aged 20-50 years, BMI 18.5-29.9 kg/m2 will be recruited into this single arm pre-post study. Participants will visit the clinic after an overnight fast for a first blood collection after which they will consume a whey protein-rich drink. A second blood collection will be performed 60 minutes after ...

Biomedicines

Macrophage-derived nitric oxide (NO) plays a critical role in atherosclerosis and presents as a p... more Macrophage-derived nitric oxide (NO) plays a critical role in atherosclerosis and presents as a potential biomarker. We assessed the uptake, distribution, and NO detection capacity of an irreversible, ruthenium-based, fluorescent NO sensor (Ru-NO) in macrophages, plasma, and atherosclerotic plaques. In vitro, incubation of Ru-NO with human THP1 monocytes and THP1-PMA macrophages caused robust uptake, detected by Ru-NO fluorescence using mass-cytometry, confocal microscopy, and flow cytometry. THP1-PMA macrophages had higher Ru-NO uptake (+13%, p < 0.05) than THP1 monocytes with increased Ru-NO fluorescence following lipopolysaccharide stimulation (+14%, p < 0.05). In mice, intraperitoneal infusion of Ru-NO found Ru-NO uptake was greater in peritoneal CD11b+F4/80+ macrophages (+61%, p < 0.01) than CD11b+F4/80− monocytes. Infusion of Ru-NO into Apoe−/− mice fed high-cholesterol diet (HCD) revealed Ru-NO fluorescence co-localised with atherosclerotic plaque macrophages. When R...

Il est maintenant bien établi que le vieillissement est lié à l’apparition de troubles cognitifs.... more Il est maintenant bien établi que le vieillissement est lié à l’apparition de troubles cognitifs. Ces altérations mnésiques liées à l’âge peuvent être mises en évidence à la fois chez l’Homme et l’animal. Plusieurs études ont pu mettre en évidence le rôle bénéfique des polyphénols sur les fonctions mnésiques et en particulier sur le déclin mnésique lié au vieillissement. Ainsi, le projet Neurophénols a pour objectif de mettre au point des actifs nutritionnels riches en polyphénols provenant de raisin et de bleuet, et d’objectiver leur rôle bénéfique sur le déclin cognitif lié à l’âge chez l’Homme et les animaux de compagnie. L’objectif de cette thèse était de mettre en évidence des effets bénéfiques d’un mélange de polyphénols de raisin et de bleuet, l’extrait Neurophenol®, sur les performances d’apprentissage et de mémoire chez la souris âgée et mieux comprendre les mécanismes neurobiologiques sous-tendant ces performances. Nous avons plus spécifiquement ciblé l’hippocampe, structu...

Objective: To investigate the optimal combination of dietary polyphenols associated with the long... more Objective: To investigate the optimal combination of dietary polyphenols associated with the long-term risk of dementia in a large prospective French cohort of older persons, the Three-City (3C) Study. Methods: We included 1,329 non-demented older adults from the 3C Study with assessment of intake of 26 polyphenol subclasses and followed for 12 years for dementia. Using Partial Least Square for Cox models, we identified a pattern of polyphenol intake associated with dementia risk. Results: The pattern combined several flavonoids (dihydroflavonols, anthocyanins, isoflavonoids, flavanones), stilbenes (including resveratrol), lignans and other subclasses (hydroxybenzaldehydes, naphtoquinones, furanocoumarins). Compared with participants in the lower quintile of pattern score, those in the higher quintile had a 50% lower risk of dementia (95% CI 20%; 68%, p-trend <0.01) in multivariate models. Conclusions: In this French cohort, a polyphenol pattern provided by a diet containing specific plant products (nuts, citrus, berries, leafy vegetables, soy, cereals, olive oil) accompanied with red wine and tea was associated with lower dementia risk

Il est maintenant bien établi que le vieillissement est lié à l'apparition de troubles cognitifs.... more Il est maintenant bien établi que le vieillissement est lié à l'apparition de troubles cognitifs. Ces altérations mnésiques liées à l'âge peuvent être mises en évidence à la fois chez l'Homme et l'animal. Plusieurs études ont évoqué le rôle bénéfique des polyphénols sur les fonctions mnésiques et en particulier sur le déclin cognitif lié à l'âge. Le projet Neurophenols a permis de mettre au point un mélange de polyphénols extraits de raisins et de bleuets (PEGB) et d'objectiver son rôle bénéfique sur le déclin cognitif lié à l'âge au niveau préclinique et clinique. Au niveau préclinique, chez la souris, la consommation de PEGB par voie alimentaire permet de normaliser les performances d'apprentissage et de mémoire dépendant de l'hippocampe, altérées au cours du vieillissement. Cet effet bénéfique est aussi mis en évidence sur l'expression de marqueurs moléculaires impliqués dans la plasticité synaptique et la neurogenèse hippocampique, processus qui sous-tendent les processus mnésiques. Ces résultats précliniques prometteurs ont été prolongés par une étude d'intervention nutritionnelle chez l'homme pour l'évaluation des effets de PEGB sur la mémoire de sujets âgés.

IBRO Neuroscience Reports, 2022

Lysosomal network abnormalities are an increasingly recognised feature of Alzheimer’s disease (AD... more Lysosomal network abnormalities are an increasingly recognised feature of Alzheimer’s disease (AD), which appear early and are progressive in nature. Sandhoff disease and Tay-Sachs disease (neurological lysosomal storage diseases caused by mutations in genes that code for critical subunits of β-hexosaminidase) result in accumulation of amyloid-β (Aβ) and related proteolytic fragments in the brain. However, experiments that determine whether mutations in genes that code for β-hexosaminidase are risk factors for AD are currently lacking. To determine the relationship between β-hexosaminidase and AD, we investigated whether a heterozygous deletion of Hexb, the gene that encodes the beta subunit of β-hexosaminidase, modifies the behavioural phenotype and appearance of disease lesions in AppNL-G-F/NL-G-F(AppKI/KI) mice. AppKI/KI and Hexb+/- mice were crossed and evaluated in a behavioural test battery. Neuropathological hallmarks of AD and ganglioside levels in the brain were also examined. Heterozygosity of Hexb in AppKI/KI mice reduced learning flexibility during the Reversal Phase of the Morris water maze. Contrary to expectation, heterozygosity of Hexb caused a small but significant decrease in amyloid beta deposition and an increase in the microglial marker IBA1 that was region- and age-specific. Hexb heterozygosity caused detectable changes in the brain and in the behaviour of an AD model mouse, consistent with previous reports that described a biochemical relationship between HEXB and AD. This study reveals that the lysosomal enzyme gene Hexb is not haplosufficient in the mouse AD brain.

FEBS Open Bio, 2021

Age‐related diseases represent some of the largest unmet clinical needs of our time. While treatm... more Age‐related diseases represent some of the largest unmet clinical needs of our time. While treatment of specific disease‐related signs has had some success (for example, the effect of statin drugs on slowing progression of atherosclerosis), slowing biological ageing itself represents a target that could significantly increase health span and reduce the prevalence of multiple age‐related diseases. Mechanistic target of rapamycin complex 1 (mTORC1) is known to control fundamental processes in ageing: inhibiting this signalling complex slows biological ageing, reduces age‐related disease pathology and increases lifespan in model organisms. How mTORC1 inhibition achieves this is still subject to ongoing research. However, one mechanism by which mTORC1 inhibition is thought to slow ageing is by activating the autophagy–lysosome pathway. In this review, we examine the special bidirectional relationship between mTORC1 and the lysosome. In cells, mTORC1 is located on lysosomes. From this ad...

The invention relates to a nutritional or therapeutic agent comprising a mixture of molecules obt... more The invention relates to a nutritional or therapeutic agent comprising a mixture of molecules obtained from Vitis vinifera and Vaccinium angustifolium, comprising: - at least 1% of catechins and epicatechins, the proportion being given by weight relative to the total weight of the mixture , preferably at least 5%, and - at least 5 ppm (parts per million in the mixture) of ferulic acid, preferably at least 10 ppm. The invention also relates to the use of this agent for its effects on cognitive function in particular.

Il est maintenant bien etabli que le vieillissement est lie a l’apparition de troubles cognitifs.... more Il est maintenant bien etabli que le vieillissement est lie a l’apparition de troubles cognitifs. Ces alterations mnesiques liees a l’âge peuvent etre mises en evidence a la fois chez l’Homme et l’animal. Plusieurs etudes ont pu mettre en evidence le role benefique des polyphenols sur les fonctions mnesiques et en particulier sur le declin mnesique lie au vieillissement. Ainsi, le projet Neurophenols a pour objectif de mettre au point des actifs nutritionnels riches en polyphenols provenant de raisin et de bleuet, et d’objectiver leur role benefique sur le declin cognitif lie a l’âge chez l’Homme et les animaux de compagnie. L’objectif de cette these etait de mettre en evidence des effets benefiques d’un melange de polyphenols de raisin et de bleuet, l’extrait Neurophenol®, sur les performances d’apprentissage et de memoire chez la souris âgee et mieux comprendre les mecanismes neurobiologiques sous-tendant ces performances. Nous avons plus specifiquement cible l’hippocampe, structu...

Trends in Molecular Medicine, 2021

Preclinical research shows that autophagy is a modifiable process that holds promise for preventi... more Preclinical research shows that autophagy is a modifiable process that holds promise for preventing human age-related disease. However, this knowledge has not been clinically translated. Here, we discuss recent developments in the ability to measure human autophagy, and why it is a critical step for translation.