👤 Sandrine Aubert

Amyloid-β (Aβ) plays a critical role in Alzheimer's disease (AD) and its accumulation in the brain is pivotal to disease progression and precedes memory and neuronal loss. Besides the severely handicapping brain symptoms, AD patients display early gastro-intestinal (GI) manifestations such as upper and lower GI dysmotility, in particular constipation. Although there is increasing evidence of Aβ accumulation in the gut, its pathogenic effects on enteric nervous system (ENS) connectivity and gut function as well as underlying pathophysiological mechanisms are poorly understood. Furthermore, studies have reported a gut to brain transmission of Aβ that causes memory deficits in mice. Therefore, identifying therapeutics which can reduce Aβ accumulation in the gut at an early stage of the disease could have the advantage of slowing or even reversing disease progression before severe alterations or irreversible damages at both intestinal and brain levels. Hence, in this study, we investigated the capacity of the short-fatty acid butyrate to restore Aβ-driven alteration of ENS connectivity and gut-brain functions in the SAMP8 mouse model of AD. Here we show that SAMP8 mice display a gut amyloid pathology, an alteration of ENS connectivity and gut defects prior to memory decline. BACE1, an Aβ-producing enzyme, expression and activity are increased whereas neprilysin, an Aβ-degrading enzyme, is decreased in the gut of SAMP8 mice, indicating a rise in the Amyloid Precursor Protein (APP) holoprotein processing and a reduction of Aβ clearance which promote an amyloidosis. In primary ENS cultures, Aβ causes a degradation of synaptic-associated proteins EphB2 and synaptophysin, leading to an alteration of ENS connectivity. In wild-type mice, intra-colon delivery of Aβ alters ENS connectivity and causes subsequent GI symptoms, recapitulating the phenotype of the SAMP8 mouse model of aging and AD. Moreover, Aβ impairs ENS connectivity in human induced pluripotent stem cell (iPSC)-derived intestinal organoids and explant cultures of human colon, indicating that Aβ causes ENS lesions in models of the human gut. Butyrate, a short-chain fatty acid derived from bacterial metabolism, reduces Aβ secretion and preserves enteric neuronal connectivity in vitro and in vivo, and blocks Aβ accumulation in the gut, brain and plasma in SAMP8 mice. In addition, butyrate ameliorates neuroinflammation and prevents gut dysfunction and memory deficit. Collectively, these findings suggest that Aβ promotes gut symptoms through alteration of ENS connectivity and butyrate counteracts these impairments with an amelioration of neuroinflammation and memory function in AD model. Show less

An emerging approach in surgery is to propose prehabilitation programs to strengthen the patient's functional abilities before surgical interventions, thus helping them cope better with its consequences. In drug-resistant language-dominant temporal lobe epilepsy (LdTLE), surgical treatment carries a risk of increasing cognitive deficits, notably word-finding difficulties (anomia) and verbal memory difficulties that negatively impact personal, social, and occupational activities. In this study, we invited 15 LdTLE patients to enroll in a speech and language prehabilitation program adapted to the specifics of their difficulties, organized daily during the preoperative period. Naming performance (for trained and untrained words) was studied twice before prehabilitation, during prehabilitation, and 1 week and 6 months after surgery. Results were analyzed using a generalized linear mixed effects model. We found a significant effect of prehabilitation on trained items before surgery. Postoperatively, trained items showed a slight and nonsignificant performance increase compared to baseline, whereas untrained items showed a significant decline in the same comparison. We conclude that trained words were better protected from postsurgical decline than untrained words. Our research can contribute to patient support during surgical decision-making; ultimately, prehabilitation might be considered as part of individualized care. These encouraging results lay the groundwork for more detailed or powerful examinations of the protective effect of prehabilitation on language skills. Show less

Mitochondria are essential organelles required for several cellular processes ranging from ATP production to cell maintenance. To provide energy, mitochondria are transported to specific cellular areas in need. Mitochondria also need to be recycled. These mechanisms rely heavily on trafficking events. While mechanisms are still unclear, hypothalamic mitochondria are linked to obesity. We used C2 domain protein 5 (C2CD5, also called C2 domain-containing phosphoprotein [CDP138]) whole-body KO mice primary neuronal cultures and cell lines to perform electron microscopy, live cellular imaging, and oxygen consumption assay to better characterize mitochondrial alteration linked to C2CD5. This study identified that C2CD5 is necessary for proper mitochondrial trafficking, structure, and function in the hypothalamic neurons. We previously reported that mice lacking C2CD5 were obese and displayed reduced functional G-coupled receptor, melanocortin receptor 4 (MC4R) at the surface of hypothalamic neurons. Our data suggest that in neurons, normal MC4R endocytosis/trafficking necessities functional mitochondria. Our data show that C2CD5 is a new protein necessary for normal mitochondrial function in the hypothalamus. Its loss alters mitochondrial ultrastructure, localization, and activity within the hypothalamic neurons. C2CD5 may represent a new protein linking hypothalamic dysfunction, mitochondria, and obesity. Show less

Hypertriglyceridemia (HTG) is known as a common metabolic disorder associated with increased production, decrease catabolism and/or decreased hepatic uptake of triglyceride (TG)-rich particles. We assessed, in the Quebec City population, the allele frequency and haplotype distributions of mutations in genes related to HTG, such as the apolipoprotein E (APOE) (C112R and C158R), the apolipoprotein CIII (APOC3) (C-482T and C3238G) and the peroxisome proliferator-activated receptor alpha (PPARalpha) (L162V) genes. A total of 938 anonymous unlinked newborns from the metropolitan Quebec City area have been genotyped. Allele frequencies observed in the Quebec City population differed from known frequencies determined in other Caucasian populations. The co-transmitted allele distribution between the two-marker genotypes APOE/APOC3(C3238G) and APOC3(C-482T)/PPARalpha(L162V) presented a weak deviation from the assumption of genetic independence. Also, we observed a non-independent distribution of the T-482/G3238 allele combinations within the APOC3 gene, suggesting strong linkage disequilibrium between the C-482T and C3238G polymorphisms. Moreover, comparisons of allele frequencies observed in the population of Québec City to those obtained in other Caucasian populations suggested that the population of Québec City may be at a lower risk of developing HTG due to APOE, APOC3 and PPARalpha genetic variants. However, the strong linkage disequilibrium and the two-marker genotype distributions observed in the APOC3 gene suggest that these two variants may functionally interact in the Québec City population. Show less