Research paper

Microglial lipid phosphatase SHIP1 limits complement-mediated synaptic pruning... 14 January 2025

Alessandro Matera, Anne-Claire Compagnion, Chiara Pedicone, Janssen M Kotah, Andranik Ivanov, Katia Monsorno, Gwenaël Labouèbe, Loredana Leggio, Marta Pereira-Iglesias, Dieter Beule, Virginie Mansuy-Aubert, Tim L Williams, Nunzio Iraci, Amanda Sierra, Samuele G Marro, Alison M Goate, Bart J L Eggen, William G Kerr, Rosa C Paolicelli

The gene inositol polyphosphate-5-phosphatase D (INPP5D), which encodes the lipid phosphatase SH2-containing inositol polyphosphate 5-phosphatase 1 (SHIP1), is associated with the risk of Alzheimer’s disease (AD). How it influences microglial function and brain physiology is unclear. Here, we showed that SHIP1 was enriched in early stages of healthy brain development. By combining in vivo loss-of-function approaches and proteomics, we discovered that mice conditionally lacking microglial SHIP1 displayed increased complement and synapse loss in the early postnatal brain. SHIP1-deficient microglia showed altered transcriptional signatures and abnormal synaptic pruning that was dependent on the complement system. Mice exhibited cognitive defects in adulthood only when microglial SHIP1 was depleted early postnatally but not at later stages. Induced pluripotent stem cell (iPSC)-derived microglia lacking SHIP1 also showed increased engulfment of synaptic structures. These findings suggest that SHIP1 is essential for proper microglia-mediated synapse remodeling in the healthy developing brain. Disrupting this process has lasting behavioral effects and may be linked to vulnerability to neurodegeneration.

Neuronal LXR Regulates Neuregulin 1 Expression and Sciatic... 17 April 2020

Gavini CK, Bonomo R, Mansuy-Aubert V

Neuronal LXRs may regulate non-neuronal cell function via a Nrg1-dependent mechanism. The decrease in Nrg1 expression in DRG neurons of WD-fed mice may suggest an altered Nrg1-dependent neuron-SC communication in Obesity. The communication between neurons and non-neuronal cells such as SC could be a new biological pathway to study and understand the molecular and cellular mechanism underlying Obesity-associated neuropathy and PNS dysfunction.

Monitoring of Inflammation Reveals Tissue and Sex-specific Responses... 30 May 2022

Raiza Bonomo, Sarah Talley, Jomana Hatahet, Chaitanya Gavini, Tyler Cook, Ben Chun, Pete Kekenes-Huskey, Gregory Aubert, Edward Campbell, Virginie Mansuy-Aubert

We observed tissue- and sex- specific caspase-1 activation patterns in obese mice and treated with butyrate. Our work utilizing a caspase-1 biosensor mouse model, flow cytometry and computational analyses and offers new mechanistic insights underlying the effect of butyrate in obesity and its complications.

GnRH neurons recruit astrocytes in infancy to facilitate... 24 January 2022

Giuliana Pellegrino, Marion Martin, Cécile Allet, Tori Lhomme, Sarah Geller, Delphine Franssen, Virginie Mansuy, Maria Manfredi-Lozano, Adrian Coutteau-Robles, Virginia Delli, S. Rasika, Danièle Mazur, Anne Loyens, Manuel Tena-Sempere, Juergen Siepmann, François P. Pralong, Philippe Ciofi, Gabriel Corfas, Anne-Simone Parent, Sergio R. Ojeda, Ariane Sharif & Vincent Prevot

These findings uncover a previously unknown neuron-to-neural-progenitor communication pathway and demonstrate that postnatal astrogenesis is a basic component of a complex set of mechanisms used by the neuroendocrine brain to control sexual maturation.

LXR agonist Prevents Peripheral Neuropathy and modifies PNS... 22 February 2022

Chaitanya K. Gavini, Nadia Elshareif, Anand V. Germanwala, Gregory Aubert, Nigel A. Calcutt, Virginie Mansuy-Aubert

Our results suggest that activation of the LXR may block the progression of neuropathy associated with aging by modifying nerve-immune cell cholesterol, thereby providing new pathways to target in efforts to delay neuropathy during aging.

LXR agonist modifies neuronal lipid homeostasis and decreases... 12 October 2022

GW3965 decreased prostaglandin levels and decreased free fatty acid content, while increasing lysophosphatidylcholine, phosphatidylcholine, and cholesterol ester species in the sensory neurons of the dorsal root ganglia (DRG). These data suggest novel downstream interplaying mechanisms that modifies DRG neuronal lipid following GW3965 treatment.

Fecal microbiome transplantation and tributyrin improves early cardiac... 2 March 2023

Fecal microbiome transplantation and tributyrin improves early cardiac dysfunction and modifies the BCAA metabolic pathway in a diet induced pre-HFpEF mouse model

More than 50% of patients with heart failure present with heart failure with preserved ejection fraction (HFpEF), and 80% of them are overweight or obese. In this study we developed an obesity associated pre-HFpEF mouse model and showed an improvement in both systolic and diastolic early dysfunction following fecal microbiome transplant (FMT). Our study suggests that the gut microbiome-derived short-chain fatty acid butyrate plays a significant role in this improvement.

Comparison of western diet-induced obesity and streptozotocin mouse... 4 June 2024

Elshareif N, Gornick E, Gavini CK, Aubert G, Mansuy-Aubert V.

Front Physiol. 2023 Oct 11;14:1238120. doi: 10.3389/fphys.2023.1238120. PMID: 37885804; PMCID: PMC10598778.

Elshareif N, Gornick E, Gavini CK, Aubert G, Mansuy-Aubert V.

In our research, we thoroughly characterized energy balance and glucose homeostasis, as well as allodynia and cardiac function, all of which have been previously shown to be altered by WD feeding. Notably, our findings revealed that the treatment of WD-fed mice with STZ exacerbated dysfunction in glucose homeostasis via reduced insulin secretion in addition to impaired peripheral insulin signaling. Furthermore, both WD and WD + STZ mice exhibited the same degree of cardiac autonomic neuropathy, such as reduced heart rate variability and decreased protein levels of cardiac autonomic markers. Furthermore, both groups developed the same symptoms of neuropathic pain, accompanied by elevated levels of activating transcription factor 3 (Atf3) in the dorsal root ganglia. These discoveries enhance our understanding of metabolic activity, insulin resistance, neuropathy, and cardiac dysfunction of diet-induced models of obesity and diabetes.