Biology subjects

Aumont, A.

Publications and source records attributed to Aumont, A..

5 recordsLinked to original sources

bioRxiv2025

In vivo inhibition of stearoyl-CoA desaturase modulates the hippocampal fatty acid profile and restores density of dendritic spines in the aggressive 5xFAD model of Alzheimer s disease

While alterations in brain lipids are a central feature of Alzheimers disease (AD), therapeutic strategies targeting brain lipid metabolism are still lacking. Prior preclinical work has shown that pharmacological inhibition of the fatty acid desaturase, stearoyl-CoA desaturase (SCD), leads to recovery of hippocampal synapses with associated improvements in learning and memory in the slow-progressing 3xTg AD mouse model. Here, we used the rapidly progressing, highly amyloidogenic 5xFAD AD model to further delve into the effect of the SCD inhibitor (SCDi) on AD-associated fatty acid alterations and synapse loss. Hippocampus, cortex and plasma samples were collected from male and female 5xFAD and non-carrier control mice for fatty acid profiling and assessment of disease hallmarks. Plaque pathology, gliosis, and fatty acid alterations that included an increase in the C16:1/C16:0 desaturation index, a measure of SCD enzymatic activity, were apparent in the female hippocampus at 5 months of age, with similar fatty acid changes appearing in males by 8 months. Intracerebroventricular infusion of SCDi via osmotic pump for 28 days in 5 months old female 5xFAD and NC mice modulated the SCD-related fatty acid disturbances as well as PUFA concentrations. Quantification of Golgi staining revealed an SCDi-induced recovery of dendritic spine density. The beneficial effects of SCDi treatment on fatty acid balance and hippocampal dendritic spines in this more aggressive amyloidogenic 5xFAD model further support SCD inhibition as a promising therapeutic avenue for AD.

neuroscience↗

bioRxiv2025

Ketogenic interventions prevent alterations of the gut microbiome in transgenic Alzheimer Disease mice

Alterations in the gut microbiome constitute a feature of aging and therefore represent a therapeutic target for aging-related diseases. In this study, we investigated the impact of ketogenic interventions on the microbiome of mice genetically predisposed to Alzheimers disease (AD). AD mice exhibited several microbial alterations, notably increased levels of Bifidobacterium and decreased levels of Bacteroidetes. Ketogenic interventions, either a medium-chain triglyceride-enriched diet (MCT) or carbohydrate-free high-fat diet (CFHF), administered for 1 month restored the levels of more than 50% of the bacteria altered in AD mice, including a strong reduction in Bifidobacterium levels. Ketogenic interventions induced a shift in the gut microbiome associated with increased levels of short-chain fatty acid-producing bacteria, such as Lachnospiraceae and Muribaculaceae. MCT and CFHF also triggered diet-specific microbial changes, which may contribute to the distinct physiological effects of these diets. In conclusion, ketogenic interventions may influence AD pathophysiology by modulating the gut microbiome.

neuroscience↗

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↗

bioRxiv2024

More is better: A simple antibody-based strategy for recovering all major mouse brain cell types from multiplexed single-cell RNAseq samples.

Single-cell RNA sequencing (scRNAseq) is a powerful yet costly technique for studying cellular diversity within the complexity of organs and tissues. Here, we sought to establish an effective multiplexing strategy for the adult mouse brain that could allow multiple experimental groups to be pooled into a single sample for sequencing, reducing costs, increasing data yield, and eliminating batch effects. We first describe an optimized cold temperature single-cell dissociation protocol that permits isolation of a high yield and viability of brain cells from the adult mouse. Cells isolated using this protocol were then screened by flow cytometry using a panel of antibodies, allowing identification of a single antibody, anti-Thy1.2, that can tag the vast majority of isolated mouse brain cells. We then used this primary antibody against a "universal" neural target, together with secondary antibodies carrying sample-specific oligonucleotides and the BD Rhapsody single-cell system and show that multiple adult mouse brain samples can be pooled into a single multiplexed run for scRNAseq. Bioinformatic analyses enable efficient demultiplexing of the sequenced pooled brain sample, with high tagging efficiency and precise annotation and clustering of brain cell populations. The efficiency and flexibility of the cell dissociation protocol and the two-step multiplexing strategy simplifies experimental design, optimizes reagent usage, eliminates sequencing batch effects and reduces overall experimental costs.

molecular biology↗

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↗