Biology subjects

Galoppin, M.

Publications and source records attributed to Galoppin, M..

4 recordsLinked to original sources

bioRxiv2024

Ketogenic interventions restore cognition and modulate peripheral metabolic dysfunctions in Alzheimer's disease mouse models

Lifestyle factors modulate dementia risk. We investigated mechanisms of dementia risk reduction by emerging dietary ketogenic interventions. We show that distinct interventions, a medium-chain triglycerides (MCT)-enriched diet and a carbohydrate-free, high-fat diet (CFHF), improve cognition and dendritic spine density of memory-associated hippocampal neurons in two mouse models of Alzheimers disease (AD). Only the CFHF diet drove increased circulating ketones, suggesting distinct underlying mechanisms. AD mice exhibited baseline and diet-induced susceptibility to peripheral metabolic disturbances that were improved by MCT and exacerbated by CFHF diets. Prominent AD-associated dysregulation of the liver transcriptome was largely restored by both interventions, but MCT also downregulated lipogenic enzymes and did not trigger a CFHF-like inflammatory signature. Novel AD- and diet-induced plasmatic changes in hormones and lipid species were identified. Thus, different ketogenic interventions yield cognitive benefits in AD models while showing intervention-specific modulation of peripheral metabolic defects, with implications for design of therapeutic ketogenic strategies.

neuroscience↗

bioRxiv2023

CITE-seq reveals inhibition of NF-kB pathway in B cells from vitamin D-treated multiple sclerosis patients

Vitamin D deficiency is a recognized risk factor for multiple sclerosis (MS) and has been associated with disease activity and progression. Vitamin D treatment has emerged as potentially protective, despite conflicting results from randomized controlled trials. Here, we used single-cell RNA-sequencing (scRNA-seq) combined with barcoded antibodies targeting surface markers (CITE-seq) to uncover candidate genes and pathways regulated in PBMC subpopulations from MS patients receiving high-dose vitamin D (n=5) or placebo (n=5). Best candidates were combined with genes involved in immune function and vitamin D metabolism for validation in a new cohort (n=8 in each group) by high-throughput quantitative polymerase chain reaction (HT-qPCR) in FACS-sorted naive CD4, Th1, Th17, Treg, naive CD8, memory and naive B cells, and MAIT cells. CITE-seq revealed no significant changes in the proportions of these subpopulations in response to vitamin D treatment. Out of the 92 candidate genes identified by CITE-seq, we validated differential expression of five genes (UXT, SNRPN, SUB1, GNLY and KLF6) using HT-qPCR. Furthermore, CITE-seq uncovered vitamin D-induced regulation of several pathways in naive and memory B cells, including MAPK, TLR and interleukin pathways, that may contribute to counteract Epstein-Barr virus (EBV)-induced resistance to apoptosis, notably through inhibition of the NF-{kappa}B pathway. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/559400v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1ad28c1org.highwire.dtl.DTLVardef@14ed135org.highwire.dtl.DTLVardef@188fea1org.highwire.dtl.DTLVardef@105353c_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2023

Central inhibition of Stearoyl-CoA Desaturase has minimal effects on the peripheral metabolic symptoms of the 3xTg Alzheimer's disease mouse model

Evidence from genetic and epidemiological studies point to lipid metabolism defects in both the brain and periphery being at the core of Alzheimers disease (AD) pathogenesis. Previously, we reported that central inhibition of the rate-limiting enzyme in monounsaturated fatty acid synthesis, Stearoyl-CoA Desaturase (SCD), improves brain structure and function in the 3xTg mouse model of AD (3xTg-AD). Here, we tested whether these beneficial central effects involve recovery of peripheral metabolic defects, such as fat accumulation and glucose and insulin handling. As early as 3 months of age, 3xTg-AD mice exhibited obesity-like phenotypes including increased body weight and visceral and subcutaneous white adipose tissue deposition, as well as diabetic-like peripheral gluco-regulatory abnormalities. Intracerebral infusion of an SCD inhibitor that normalizes brain fatty acid metabolism, synapse loss and learning and memory deficits in middle-aged symptomatic 3xTg-AD mice did not affect peripheral phenotypes. This suggests that the beneficial effects of central SCD inhibition on cognitive function are not mediated by recovery of peripheral metabolic abnormalities. Given the widespread side-effects of systemically administered SCD inhibitors, these data suggest that selective inhibition of SCD in the brain may represent a clinically safer and more effective strategy for AD.

neuroscience↗

bioRxiv2023

Syndecan-1 as specific cerebrospinal fluid biomarker of multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease often characterized by remission and relapse periods occurring at irregular intervals after an initial attack (clinically isolated syndrome) and followed by a gradual progression of disability. Clinical symptoms, magnetic resonance imaging and abnormalities in cerebrospinal fluid (CSF) immunoglobulin profile allow diagnosis with a good sensitivity. However, current biomarkers lack specificity or have poor individual prognostic value. To identify novel candidate biomarkers of MS, we analysed 1) the CSF proteome from symptomatic controls and patients with clinically isolated syndrome or remitting-relapsing multiple sclerosis (n=40), and 2) changes in oligodendrocyte secretome upon proinflammatory or pro-apoptotic treatment. Proteins exhibiting differences in abundance in both studies were combined with previously described MS biomarkers to build a list of 87 proteins that were quantified by parallel reaction monitoring (PRM) in CSF samples from a new cohort comprising symptomatic controls and MS patients at different disease stages (n=60). The eleven proteins that passed this qualification step were subjected to a new PRM assay from a larger cohort (n=158) comprising patients with MS at different disease stages or with other inflammatory or non-inflammatory neurological disorders. Collectively, these studies identified a biomarker signature of MS that might improve MS diagnosis and prognosis. These include the oligodendrocyte precursor cell proteoglycan Syndecan-1, which was more efficient than previously described biomarkers to discriminate MS from other inflammatory and non-inflammatory neurological disorders.

neuroscience↗