👤 L Dupuy

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder thought to result from complex interactions between genetic and environmental risk factors. The APOE-ε4 allele is the strongest genetic contributor to late-onset AD, while a Western diet - high in saturated fats and refined sugars - is a major lifestyle-related risk factor associated with AD progression. However, how these two factors interact at an early stage of the disease remains unclear. In this study, we examined their combined impact on hippocampal synaptic transmission and plasticity in an AD mouse model and evaluated whether supplementation with d-serine, the key NMDAR co-agonist, could reverse the resulting deficits. To assess the combined effects of genetic and dietary risk factors on synaptic function, we crossed APP/PS1 mice with APOE-ε4 KI mice and generated four mouse lines: wild-type, APP/PS1, APOE-ε4, and APP/PS1/APOE-ε4. Hippocampal synaptic transmission and plasticity, NMDAR function and d- and l-serine levels were evaluated using a combination of electrophysiological recordings, pharmacological interventions and capillary electrophoresis in brain slices, under either control or Western diet conditions. A significant impairment of both basal excitatory synaptic transmission and long-term potentiation (LTP) was detected in APP/PS1 mice by 9 months of age. These deficits were significantly more pronounced in APP/PS1/APOE-ε4 mice. Notably, Western diet accelerated these impairments, with significant deficits already present at 7 months in both APOE-ε4 and APP/PS1/APOE-ε4 mice. Mechanistically, these impairments were associated with reduced d-serine availability and NMDAR hypofunction at CA3-CA1 synapses. This study provides direct evidence of a specific and synergistic interaction between the APOE-ε4 genotype and Western diet in advancing and exacerbating hippocampal synaptic dysfunction in an AD mouse model. These findings highlight d-serine/NMDAR signaling as a key mechanistic pathway through which genetic and environmental risk factors converge in early AD, and underscore the potential of targeting astrocytic d-serine biosynthetic pathways as a promising therapeutic strategy for APOE-ε4 carriers at risk for late-onset AD. Not applicable. The online version contains supplementary material available at 10.1186/s13195-026-01992-y. Show less

The fungal cell wall occupies a central place in the interaction between fungi and their environment. This study focuses on the role of the putative polysaccharide synthase Cps1 in the physiology, development and virulence of the grey mold-causing agent Show less

The basic understanding of the biological effects of eukaryotic translation initiation factors (EIFs) remains incomplete, notably for their roles independent of protein translation. Different EIFs exhibit nuclear localization and DNA-related functions have been proposed, but the understanding of EIFs novel functions beyond protein translation lacks of integrative analyses between the genomic and the proteomic levels. Here, the noncanonical function of EIF3F was studied in human lung adenocarcinoma by combining methods that revealed both the protein-protein and the protein-DNA interactions of this factor. We discovered that EIF3F promotes cell metastasis in vivo. The underpinning molecular mechanisms involved the regulation of a cluster of 34 metastasis-promoting genes including Snail2, as revealed by proteomics combined with immuno-affinity purification of EIF3F and ChIP-seq/Q-PCR analyses. The interaction between EIF3F and signal transducer and activator of transcription 3 (STAT3) controlled the EIF3F-mediated increase in Snail2 expression and cellular invasion, which were specifically abrogated using the STAT3 inhibitor Nifuroxazide or knockdown approaches. Furthermore, EIF3F overexpression reprogrammed energy metabolism through the activation of AMP-activated protein kinase and the stimulation of oxidative phosphorylation. Our findings demonstrate the role of EIF3F in the molecular control of cell migration, invasion, bioenergetics, and metastasis. The discovery of a role for EIF3F-STAT3 interaction in the genetic control of cell migration and metastasis in human lung adenocarcinoma could lead to the development of diagnosis and therapeutic strategies. Show less

Cholesterol is a risk factor for developing vascular pathologies, which is in turn an important risk factor for dementia. Previous studies linking lipids and dementia have yielded inconsistent results, which may be attributable to sex differences in the etiology of both vascular disease and dementia. The aim of this study was to evaluate the associations between lipids and incident dementia in 7053 community-dwelling elderly. Dementia was diagnosed at baseline, and 2, 4, and 7-year follow-up. Multivariate Cox models stratified by sex and history of vascular pathologies at baseline were adjusted for sociodemographic, mental and physical health variables, and genetic vulnerability. In men without vascular pathologies, an increased incidence of all-cause dementia but not Alzheimer's disease (AD) was associated with high triglyceride (TG) (HR = 1.55, 95% CI = 1.04-2.32, p = 0.03) and low HDL-cholesterol levels (HR = 1.49, 95% CI = 0.99-2.23, p = 0.05). In women without vascular pathologies, low TG levels were associated with a decreased risk of AD (HR = 0.65, 95% CI = 0.43-0.97, p = 0.03). A decreased risk was also found with high TG levels which may depend on genetic vulnerability to dyslipidemia related to APOA5. For both sexes, no significant associations were found between total- or LDL-cholesterol and dementia or AD. Low HDL-cholesterol and high TG levels may be risk factors of dementia in elderly men whereas low TG is associated with decreased incident AD in women. This data suggests a complex sex-specific etiology of vascular dementia and AD. Show less

Activated Ras oncogene induces DNA-damage response by triggering reactive oxygen species (ROS) production and this is critical for oncogene-induced senescence. Until now, little connections between oncogene expression, ROS-generating NADPH oxidases and DNA-damage response have emerged from different studies. Here we report that H-RasV12 positively regulates the NADPH oxidase system NOX4-p22(phox) that produces H(2)O(2). Knocking down the NADPH oxidase with small interference RNA decreases H-RasV12-induced DNA-damage response detected by γ-H2A.X foci analysis. Using HyPer, a specific probe for H(2)O(2), we detected an increase in H(2)O(2) in the nucleus correlated with NOX4-p22(phox) perinuclear localization. DNA damage response can be caused not only by H-RasV12-driven accumulation of ROS but also by a replicative stress due to a sustained oncogenic signal. Interestingly, NOX4 downregulation by siRNA abrogated H-RasV12 regulation of CDC6 expression, an essential regulator of DNA replication. Moreover, senescence markers, such as senescence-associated heterochromatin foci, PML bodies, HP1β foci and p21 expression, induced under H-RasV12 activation were decreased with NOX4 inactivation. Taken together, our data indicate that NADPH oxidase NOX4 is a critical mediator in oncogenic H-RasV12-induced DNA-damage response and subsequent senescence. Show less